|
1
|
Sajukumar K, Yadav P, Lee GH. Dab1 expression level controls Reelin-induced PI3K-Akt activation in early GABAergic neurons. Biochem Biophys Res Commun 2025; 751:151444. [PMID: 39919390 DOI: 10.1016/j.bbrc.2025.151444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 01/24/2025] [Accepted: 02/03/2025] [Indexed: 02/09/2025]
Abstract
Disabled-1 (Dab1) is a key regulator of the Reelin signaling cascades and controls many neurodevelopmental processes, including pyramidal neuron migration, dendrite growth, and spine formation. Dab1 is phosphorylated upon the binding of Reelin to Very low density lipoprotein receptor (VLDLR) and Apolipoprotein E receptor 2 (ApoER2) receptors, resulting in activation of a series of downstream signaling pathways, including Phosphoinositide 3-kinase (PI3K)/Akt, Lissencephaly 1 (Lis1), Crks/C3G, and Extracellular signal-regulated kinase 1/2 (Erk1/2). Dab1 is then rapidly degraded via the proteasome pathway. In humans, REELIN and DAB1 are genetically associated with several psychiatric disorders, such as schizophrenia and autism spectrum disorder. Although a subset of GABAergic neurons express Reelin and are continuously exposed to Reelin from early developmental stages through adulthood, most studies have only investigated the role of Reelin in the development and function of pyramidal neurons; as such the role of Reelin in GABAergic neurons remains poorly understood. In this study, we isolated primary neurons from mouse medial ganglionic eminence (MGE) at embryonic day 14.5 that 98-99 % were composed of GABAergic neurons. Using MGE-isolated GABAergic neurons, we studied the quantitative differences in Reelin signaling and expression of related genes in these neurons for the first time. Reelin supplementation did not activate PI3K-Akt signaling in most GABAergic neurons, but it did activate the signaling pathway in Somatostatin-positive GABAergic neurons. Dab1 was transcriptionally repressed in early GABAergic neurons, demonstrating the selective activation of Reelin signaling between subsets of neurons. This study provides quantitative evidence and contributes insights into the molecular mechanisms underlying the limited effects of Reelin on Dab1-related developmental activities in the majority of GABAergic neurons during brain development.
Collapse
Affiliation(s)
- Kavitha Sajukumar
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Prabhakar Yadav
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Gum Hwa Lee
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea.
| |
Collapse
|
|
2
|
Dražić Maras E, Kelam N, Racetin A, Haque E, Dražić M, Vukojević K, Katsuyama Y, Saraga-Babić M, Filipović N. Autophagy markers expression pattern in developing liver of the yotari (dab1 -/-) mice and humans. Acta Histochem 2025; 127:152224. [PMID: 39647211 DOI: 10.1016/j.acthis.2024.152224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 12/03/2024] [Accepted: 12/03/2024] [Indexed: 12/10/2024]
Abstract
Autophagy plays an important role in the physiology and pathology of the liver. Several negative autophagy regulators have been discovered, including epidermal growth factor receptor (EGFR), mediated by activation of the PI3K/Akt/mTOR signaling pathway. Disabled-1 (Dab1) is one of the mediating adaptor factors of PI3K/Akt/mTOR signaling pathways. We investigated the potential impact of Dab1 on autophagy-related markers (LC3B, LAMP2A, HSC70, and GRP78) in the developing liver by using a model of yotari mice and compared it with autophagy marker expression in human liver development. Mouse embryos were obtained at gestation days 13.5 and 15.5 (E13.5 and E15.5), and a total of 5 normal human conceptuses were obtained between gestation days 5 and 10. Histological sections were analyzed by immunohistochemistry. The highest expression of the early endosome-forming factor LC3B and the microautophagy factor LAMP2a was observed at the transition from embryonic to early fetal phase, whereas the expression of the chaperones HSC 70 and GRP78 was highest at embryonic phase. The expression patterns of three of these factors in mouse liver were different from those in human liver: the expression of LC3B was high at E13.5, that of HSC 70 at 15.5, whereas the expression of GRP78 did not change significantly. On the other hand, the expression pattern of LAMP2a was similar to that in human development and was higher at E15.5 than at E13.5. Moreover, knockout of Dab1 resulted in significantly lower expression of LC3B and LAMP2a in mouse embryo livers (at E13.5), indicating a possible role of Dab1 in regulating autophagy during embryonic development in the liver.
Collapse
Affiliation(s)
- Edita Dražić Maras
- Infectious Diseases Department, University Hospital of Split, Split 21000, Croatia
| | - Nela Kelam
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Split School of Medicine, Šoltanska 2A, Split 21000, Croatia
| | - Anita Racetin
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Split School of Medicine, Šoltanska 2A, Split 21000, Croatia
| | - Ejazul Haque
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Split School of Medicine, Šoltanska 2A, Split 21000, Croatia
| | - Maja Dražić
- Department of Internal Medicine, Cardiology, General Hospital Knin, Knin 22300, Croatia
| | - Katarina Vukojević
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Split School of Medicine, Šoltanska 2A, Split 21000, Croatia
| | - Yu Katsuyama
- Department of Anatomy, Shiga University of Medical Science, Otsu 520-2192, Japan
| | - Mirna Saraga-Babić
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Split School of Medicine, Šoltanska 2A, Split 21000, Croatia
| | - Natalija Filipović
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Split School of Medicine, Šoltanska 2A, Split 21000, Croatia.
| |
Collapse
|
|
3
|
Markiewicz R, Markiewicz-Gospodarek A, Borowski B, Trubalski M, Łoza B. Reelin Signaling and Synaptic Plasticity in Schizophrenia. Brain Sci 2023; 13:1704. [PMID: 38137152 PMCID: PMC10741648 DOI: 10.3390/brainsci13121704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/01/2023] [Accepted: 12/05/2023] [Indexed: 12/24/2023] Open
Abstract
Recent research emphasizes the significance of studying the quality of life of schizophrenia patients, considering the complex nature of the illness. Identifying neuronal markers for early diagnosis and treatment is crucial. Reelin (RELN) stands out among these markers, with genetic studies highlighting its role in mental health. Suppression of RELN expression may contribute to cognitive deficits by limiting dendritic proliferation, affecting neurogenesis, and leading to improper neuronal circuits. Although the physiological function of reelin is not fully understood, it plays a vital role in hippocampal cell stratification and neuroglia formation. This analysis explores reelin's importance in the nervous system, shedding light on its impact on mental disorders such as schizophrenia, paving the way for innovative therapeutic approaches, and at the same time, raises the following conclusions: increased methylation levels of the RELN gene in patients with a diagnosis of schizophrenia results in a multiple decrease in the expression of reelin, and monitoring of this indicator, i.e., methylation levels, can be used to monitor the severity of symptoms in the course of schizophrenia.
Collapse
Affiliation(s)
- Renata Markiewicz
- Occupational Therapy Laboratory, Chair of Nursing Development, Medical University of Lublin, 4 Staszica St., 20-081 Lublin, Poland;
| | | | - Bartosz Borowski
- Students Scientific Association, Department of Normal, Clinical and Imaging Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (B.B.); (M.T.)
| | - Mateusz Trubalski
- Students Scientific Association, Department of Normal, Clinical and Imaging Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (B.B.); (M.T.)
| | - Bartosz Łoza
- Department of Psychiatry, Medical University of Warsaw, 02-091 Warsaw, Poland;
| |
Collapse
|
|
4
|
Bracher-Smith M, Leonenko G, Baker E, Crawford K, Graham AC, Salih DA, Howell BW, Hardy J, Escott-Price V. Whole genome analysis in APOE4 homozygotes identifies the DAB1-RELN pathway in Alzheimer's disease pathogenesis. Neurobiol Aging 2022; 119:67-76. [PMID: 35977442 PMCID: PMC9548409 DOI: 10.1016/j.neurobiolaging.2022.07.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 07/04/2022] [Accepted: 07/23/2022] [Indexed: 11/20/2022]
Abstract
The APOE-ε4 allele is known to predispose to amyloid deposition and consequently is strongly associated with Alzheimer's disease (AD) risk. There is debate as to whether the APOE gene accounts for all genetic variation of the APOE locus. Another question which remains is whether APOE-ε4 carriers have other genetic factors influencing the progression of amyloid positive individuals to AD. We conducted a genome-wide association study in a sample of 5,390 APOE-ε4 homozygous (ε4ε4) individuals (288 cases and 5102 controls) aged 65 or over in the UK Biobank. We found no significant associations of SNPs in the APOE locus with AD in the sample of ε4ε4 individuals. However, we identified a novel genome-wide significant locus associated to AD, mapping to DAB1 (rs112437613, OR = 2.28, CI = 1.73-3.01, p = 5.4 × 10-9). This identification of DAB1 led us to investigate other components of the DAB1-RELN pathway for association. Analysis of the DAB1-RELN pathway indicated that the pathway itself was associated with AD, therefore suggesting an epistatic interaction between the APOE locus and the DAB1-RELN pathway.
Collapse
Affiliation(s)
- Matthew Bracher-Smith
- Division of Psychological Medicine & Clinical Neurosciences, Cardiff University, Cardiff, UK; Dementia Research Institute, Cardiff University, Cardiff, UK
| | - Ganna Leonenko
- Dementia Research Institute, Cardiff University, Cardiff, UK
| | - Emily Baker
- Dementia Research Institute, Cardiff University, Cardiff, UK
| | - Karen Crawford
- Division of Psychological Medicine & Clinical Neurosciences, Cardiff University, Cardiff, UK
| | | | - Dervis A Salih
- Dementia Research Institute, University College London, UK
| | - Brian W Howell
- Neuroscience and Physiology, State University of New York, Albany, NY, USA
| | - John Hardy
- Dementia Research Institute, University College London, UK.
| | - Valentina Escott-Price
- Division of Psychological Medicine & Clinical Neurosciences, Cardiff University, Cardiff, UK.
| |
Collapse
|
|
5
|
Lipophorin receptors regulate mushroom body development and complex behaviors in Drosophila. BMC Biol 2022; 20:198. [PMID: 36071487 PMCID: PMC9454125 DOI: 10.1186/s12915-022-01393-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 08/17/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Drosophila melanogaster lipophorin receptors (LpRs), LpR1 and LpR2, are members of the LDLR family known to mediate lipid uptake in a range of organisms from Drosophila to humans. The vertebrate orthologs of LpRs, ApoER2 and VLDL-R, function as receptors of a glycoprotein involved in development of the central nervous system, Reelin, which is not present in flies. ApoER2 and VLDL-R are associated with the development and function of the hippocampus and cerebral cortex, important association areas in the mammalian brain, as well as with neurodevelopmental and neurodegenerative disorders linked to those regions. It is currently unknown whether LpRs play similar roles in the Drosophila brain. RESULTS We report that LpR-deficient flies exhibit impaired olfactory memory and sleep patterns, which seem to reflect anatomical defects found in a critical brain association area, the mushroom bodies (MB). Moreover, cultured MB neurons respond to mammalian Reelin by increasing the complexity of their neurite arborization. This effect depends on LpRs and Dab, the Drosophila ortholog of the Reelin signaling adaptor protein Dab1. In vitro, two of the long isoforms of LpRs allow the internalization of Reelin, suggesting that Drosophila LpRs interact with human Reelin to induce downstream cellular events. CONCLUSIONS These findings demonstrate that LpRs contribute to MB development and function, supporting the existence of a LpR-dependent signaling in Drosophila, and advance our understanding of the molecular factors functioning in neural systems to generate complex behaviors in this model. Our results further emphasize the importance of Drosophila as a model to investigate the alterations in specific genes contributing to neural disorders.
Collapse
|
|
6
|
Wang G, Lei J, Wang Y, Yu J, He Y, Zhao W, Hu Z, Xu Z, Jin Y, Gu Y, Guo X, Yang B, Gao Z, Wang Z. The ZSWIM8 ubiquitin ligase regulates neurodevelopment by guarding the protein quality of intrinsically disordered Dab1. Cereb Cortex 2022; 33:3866-3881. [PMID: 35989311 DOI: 10.1093/cercor/bhac313] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/18/2022] [Accepted: 07/19/2022] [Indexed: 11/15/2022] Open
Abstract
Protein quality control (PQC) is essential for maintaining protein homeostasis and guarding the accuracy of neurodevelopment. Previously, we found that a conserved EBAX-type CRL regulates the protein quality of SAX-3/ROBO guidance receptors in Caenorhabditis elegans. Here, we report that ZSWIM8, the mammalian homolog of EBAX-1, is essential for developmental stability of mammalian brains. Conditional deletion of Zswim8 in the embryonic nervous system causes global cellular stress, partial perinatal lethality and defective migration of neural progenitor cells. CRISPR-mediated knockout of ZSWIM8 impairs spine formation and synaptogenesis in hippocampal neurons. Mechanistic studies reveal that ZSWIM8 controls protein quality of Disabled 1 (Dab1), a key signal molecule for brain development, thus protecting the signaling strength of Dab1. As a ubiquitin ligase enriched with intrinsically disordered regions (IDRs), ZSWIM8 specifically recognizes IDRs of Dab1 through a "disorder targets misorder" mechanism and eliminates misfolded Dab1 that cannot be properly phosphorylated. Adult survivors of ZSWIM8 CKO show permanent hippocampal abnormality and display severely impaired learning and memory behaviors. Altogether, our results demonstrate that ZSWIM8-mediated PQC is critical for the stability of mammalian brain development.
Collapse
Affiliation(s)
- Guan Wang
- Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China; The MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Brain Science and Brain Medicine, Hangzhou 310058, China
| | - Jing Lei
- Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China; The MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Brain Science and Brain Medicine, Hangzhou 310058, China
| | - Yifeng Wang
- Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China; The MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Brain Science and Brain Medicine, Hangzhou 310058, China
| | - Jiahui Yu
- Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China; The MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Brain Science and Brain Medicine, Hangzhou 310058, China
- Chu Kochen Honors College of Zhejiang University, Hangzhou 310058, China
| | - Yinghui He
- Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China; The MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Brain Science and Brain Medicine, Hangzhou 310058, China
| | - Weiqi Zhao
- Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China; The MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Brain Science and Brain Medicine, Hangzhou 310058, China
| | - Zhechun Hu
- Center of Stem Cell and Regenerative Medicine, and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Zhenzhong Xu
- Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China; The MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Brain Science and Brain Medicine, Hangzhou 310058, China
| | - Yishi Jin
- Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA
| | - Yan Gu
- Center of Stem Cell and Regenerative Medicine, and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Xing Guo
- The Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Bing Yang
- The Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Zhihua Gao
- Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China; The MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Brain Science and Brain Medicine, Hangzhou 310058, China
| | - Zhiping Wang
- Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China; The MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Brain Science and Brain Medicine, Hangzhou 310058, China
| |
Collapse
|
|
7
|
Passarella D, Ronci M, Di Liberto V, Zuccarini M, Mudò G, Porcile C, Frinchi M, Di Iorio P, Ulrich H, Russo C. Bidirectional Control between Cholesterol Shuttle and Purine Signal at the Central Nervous System. Int J Mol Sci 2022; 23:ijms23158683. [PMID: 35955821 PMCID: PMC9369131 DOI: 10.3390/ijms23158683] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 07/29/2022] [Accepted: 08/01/2022] [Indexed: 12/07/2022] Open
Abstract
Recent studies have highlighted the mechanisms controlling the formation of cerebral cholesterol, which is synthesized in situ primarily by astrocytes, where it is loaded onto apolipoproteins and delivered to neurons and oligodendrocytes through interactions with specific lipoprotein receptors. The “cholesterol shuttle” is influenced by numerous proteins or carbohydrates, which mainly modulate the lipoprotein receptor activity, function and signaling. These molecules, provided with enzymatic/proteolytic activity leading to the formation of peptide fragments of different sizes and specific sequences, could be also responsible for machinery malfunctions, which are associated with neurological, neurodegenerative and neurodevelopmental disorders. In this context, we have pointed out that purines, ancestral molecules acting as signal molecules and neuromodulators at the central nervous system, can influence the homeostatic machinery of the cerebral cholesterol turnover and vice versa. Evidence gathered so far indicates that purine receptors, mainly the subtypes P2Y2, P2X7 and A2A, are involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer’s and Niemann–Pick C diseases, by controlling the brain cholesterol homeostasis; in addition, alterations in cholesterol turnover can hinder the purine receptor function. Although the precise mechanisms of these interactions are currently poorly understood, the results here collected on cholesterol–purine reciprocal control could hopefully promote further research.
Collapse
Affiliation(s)
- Daniela Passarella
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, 86100 Campobasso, Italy
| | - Maurizio Ronci
- Department of Pharmacy, University of Chieti-Pescara, 66100 Chieti, Italy
| | - Valentina Di Liberto
- Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, 90133 Palermo, Italy
| | - Mariachiara Zuccarini
- Department of Medical Oral and Biotechnological Sciences, University of Chieti-Pescara, 66100 Chieti, Italy
| | - Giuseppa Mudò
- Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, 90133 Palermo, Italy
| | - Carola Porcile
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, 86100 Campobasso, Italy
| | - Monica Frinchi
- Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, 90133 Palermo, Italy
| | - Patrizia Di Iorio
- Department of Medical Oral and Biotechnological Sciences, University of Chieti-Pescara, 66100 Chieti, Italy
| | - Henning Ulrich
- Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo 05508-060, Brazil
| | - Claudio Russo
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, 86100 Campobasso, Italy
- Correspondence: ; Tel.: +39-087-440-4897
| |
Collapse
|
|
8
|
Hu L, Zhang L. Adult neural stem cells and schizophrenia. World J Stem Cells 2022; 14:219-230. [PMID: 35432739 PMCID: PMC8968214 DOI: 10.4252/wjsc.v14.i3.219] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 06/18/2021] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia (SCZ) is a devastating and complicated mental disorder accompanied by variable positive and negative symptoms and cognitive deficits. Although many genetic risk factors have been identified, SCZ is also considered as a neurodevelopmental disorder. Elucidation of the pathogenesis and the development of treatment is challenging because complex interactions occur between these genetic risk factors and environment in essential neurodevelopmental processes. Adult neural stem cells share a lot of similarities with embryonic neural stem cells and provide a promising model for studying neuronal development in adulthood. These adult neural stem cells also play an important role in cognitive functions including temporal and spatial memory encoding and context discrimination, which have been shown to be closely linked with many psychiatric disorders, such as SCZ. Here in this review, we focus on the SCZ risk genes and the key components in related signaling pathways in adult hippocampal neural stem cells and summarize their roles in adult neurogenesis and animal behaviors. We hope that this would be helpful for the understanding of the contribution of dysregulated adult neural stem cells in the pathogenesis of SCZ and for the identification of potential therapeutic targets, which could facilitate the development of novel medication and treatment.
Collapse
Affiliation(s)
- Ling Hu
- Department of Laboratory Animal Science and Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Lei Zhang
- Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center) and Department of Anatomy and Neurobiology, Tongji University School of Medicine, Shanghai 200092, China
| |
Collapse
|
|
9
|
Dab1-deficient deep layer neurons prevent Dab1-deficient superficial layer neurons from entering the cortical plate. Neurosci Res 2022; 180:23-35. [DOI: 10.1016/j.neures.2022.03.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 03/23/2022] [Accepted: 03/24/2022] [Indexed: 02/06/2023]
|
|
10
|
Camblor-Perujo S, Kononenko NL. Brain-specific functions of the endocytic machinery. FEBS J 2021; 289:2219-2246. [PMID: 33896112 DOI: 10.1111/febs.15897] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 03/29/2021] [Indexed: 12/12/2022]
Abstract
Endocytosis is an essential cellular process required for multiple physiological functions, including communication with the extracellular environment, nutrient uptake, and signaling by the cell surface receptors. In a broad sense, endocytosis is accomplished through either constitutive or ligand-induced invagination of the plasma membrane, which results in the formation of the plasma membrane-retrieved endocytic vesicles, which can either be sent for degradation to the lysosomes or recycled back to the PM. This additional function of endocytosis in membrane retrieval has been adopted by excitable cells, such as neurons, for membrane equilibrium maintenance at synapses. The last two decades were especially productive with respect to the identification of brain-specific functions of the endocytic machinery, which additionally include but not limited to regulation of neuronal differentiation and migration, maintenance of neuron morphology and synaptic plasticity, and prevention of neurotoxic aggregates spreading. In this review, we highlight the current knowledge of brain-specific functions of endocytic machinery with a specific focus on three brain cell types, neuronal progenitor cells, neurons, and glial cells.
Collapse
Affiliation(s)
| | - Natalia L Kononenko
- CECAD Cluster of Excellence, University of Cologne, Germany.,Center for Physiology & Pathophysiology, Medical Faculty, University of Cologne, Germany
| |
Collapse
|
|
11
|
Dlugosz P, Teufl M, Schwab M, Kohl KE, Nimpf J. Disabled 1 Is Part of a Signaling Pathway Activated by Epidermal Growth Factor Receptor. Int J Mol Sci 2021; 22:1745. [PMID: 33572344 PMCID: PMC7916142 DOI: 10.3390/ijms22041745] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 01/31/2021] [Accepted: 02/05/2021] [Indexed: 12/17/2022] Open
Abstract
Disabled 1 (Dab1) is an adapter protein for very low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) and an integral component of the Reelin pathway which orchestrates neuronal layering during embryonic brain development. Activation of Dab1 is induced by binding of Reelin to ApoER2 and VLDLR and phosphorylation of Dab1 mediated by Src family kinases. Here we show that Dab1 also acts as an adaptor for epidermal growth factor receptor (EGFR) and can be phosphorylated by epidermal growth factor (EGF) binding to EGFR. Phosphorylation of Dab1 depends on the kinase activity of EGFR constituting a signal pathway independent of Reelin and its receptors.
Collapse
Affiliation(s)
| | | | | | | | - Johannes Nimpf
- Max Perutz Laboratories, Department of Medical Biochemistry, Medical University Vienna, 1030 Vienna, Austria; (P.D.); (M.T.); (M.S.); (K.E.K.)
| |
Collapse
|
|
12
|
Nawa Y, Kimura H, Mori D, Kato H, Toyama M, Furuta S, Yu Y, Ishizuka K, Kushima I, Aleksic B, Arioka Y, Morikawa M, Okada T, Inada T, Kaibuchi K, Ikeda M, Iwata N, Suzuki M, Okahisa Y, Egawa J, Someya T, Nishimura F, Sasaki T, Ozaki N. Rare single-nucleotide DAB1 variants and their contribution to Schizophrenia and autism spectrum disorder susceptibility. Hum Genome Var 2020; 7:37. [PMID: 33298905 PMCID: PMC7655853 DOI: 10.1038/s41439-020-00125-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 09/24/2020] [Accepted: 09/27/2020] [Indexed: 01/09/2023] Open
Abstract
Disabled 1 (DAB1) is an intracellular adaptor protein in the Reelin signaling pathway and plays an essential role in correct neuronal migration and layer formation in the developing brain. DAB1 has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in genetic, animal, and postmortem studies. Recently, increasing attention has been given to rare single-nucleotide variants (SNVs) found by deep sequencing of candidate genes. In this study, we performed exon-targeted resequencing of DAB1 in 370 SCZ and 192 ASD patients using next-generation sequencing technology to identify rare SNVs with a minor allele frequency <1%. We detected two rare missense mutations (G382C, V129I) and then performed a genetic association study in a sample comprising 1763 SCZ, 380 ASD, and 2190 healthy control subjects. Although no statistically significant association with the detected mutations was observed for either SCZ or ASD, G382C was found only in the case group, and in silico analyses and in vitro functional assays suggested that G382C alters the function of the DAB1 protein. The rare variants of DAB1 found in the present study should be studied further to elucidate their potential functional relevance to the pathophysiology of SCZ and ASD.
Collapse
Affiliation(s)
- Yoshihiro Nawa
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Hiroki Kimura
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
| | - Daisuke Mori
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
- Brain and Mind Research Center, Nagoya University, Nagoya, Aichi, Japan
| | - Hidekazu Kato
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Miho Toyama
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Sho Furuta
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Yanjie Yu
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Kanako Ishizuka
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Itaru Kushima
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
- Institute for Advanced Research, Nagoya University, Nagoya, Aichi, Japan
| | - Branko Aleksic
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Yuko Arioka
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
- Institute for Advanced Research, Nagoya University, Nagoya, Aichi, Japan
- Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Aichi, Japan
| | - Mako Morikawa
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Takashi Okada
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Toshiya Inada
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Kozo Kaibuchi
- Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Masashi Ikeda
- Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Nakao Iwata
- Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Michio Suzuki
- Department of Neuropsychiatry, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan
| | - Yuko Okahisa
- Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Jun Egawa
- Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Toshiyuki Someya
- Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Fumichika Nishimura
- Office for Mental Health Support, Center for Research on Counseling and Support Services, The University of Tokyo, Tokyo, Japan
| | - Tsukasa Sasaki
- Department of Physical and Health Education, Graduate School of Education, The University of Tokyo, Tokyo, Japan
| | - Norio Ozaki
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| |
Collapse
|
|
13
|
Song W, Gottschalk CJ, Tang TX, Biscardi A, Ellena JF, Finkielstein CV, Brown AM, Capelluto DGS. Structural, in silico, and functional analysis of a Disabled-2-derived peptide for recognition of sulfatides. Sci Rep 2020; 10:13520. [PMID: 32782308 PMCID: PMC7421900 DOI: 10.1038/s41598-020-70478-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 07/16/2020] [Indexed: 01/08/2023] Open
Abstract
Disabled-2 (Dab2) is an adaptor protein that regulates the extent of platelet aggregation by two mechanisms. In the first mechanism, Dab2 intracellularly downregulates the integrin αIIbβ3 receptor, converting it to a low affinity state for adhesion and aggregation processes. In the second mechanism, Dab2 is released extracellularly and interacts with the pro-aggregatory mediators, the integrin αIIbβ3 receptor and sulfatides, blocking their association to fibrinogen and P-selectin, respectively. Our previous research indicated that a 35-amino acid region within Dab2, which we refer to as the sulfatide-binding peptide (SBP), contains two potential sulfatide-binding motifs represented by two consecutive polybasic regions. Using molecular docking, nuclear magnetic resonance, lipid-binding assays, and surface plasmon resonance, this work identifies the critical Dab2 residues within SBP that are responsible for sulfatide binding. Molecular docking suggested that a hydrophilic region, primarily mediated by R42, is responsible for interaction with the sulfatide headgroup, whereas the C-terminal polybasic region contributes to interactions with acyl chains. Furthermore, we demonstrated that, in Dab2 SBP, R42 significantly contributes to the inhibition of platelet P-selectin surface expression. The Dab2 SBP residues that interact with sulfatides resemble those described for sphingolipid-binding in other proteins, suggesting that sulfatide-binding proteins share common binding mechanisms.
Collapse
Affiliation(s)
- Wei Song
- Protein Signaling Domains Laboratory, Department of Biological Sciences, Fralin Life Sciences Institute, and Center for Soft Matter and Biological Physics, Virginia Tech, Blacksburg, VA, 24061, USA
| | - Carter J Gottschalk
- Research and Informatics, University Libraries, Biochemistry Department, and Center for Drug Discovery, Virginia Tech, Blacksburg, 24061, VA, USA
| | - Tuo-Xian Tang
- Protein Signaling Domains Laboratory, Department of Biological Sciences, Fralin Life Sciences Institute, and Center for Soft Matter and Biological Physics, Virginia Tech, Blacksburg, VA, 24061, USA
| | - Andrew Biscardi
- Protein Signaling Domains Laboratory, Department of Biological Sciences, Fralin Life Sciences Institute, and Center for Soft Matter and Biological Physics, Virginia Tech, Blacksburg, VA, 24061, USA
| | - Jeffrey F Ellena
- Biomolecular Magnetic Resonance Facility, University of Virginia, Charlottesville, VA, 22904, USA
| | - Carla V Finkielstein
- Integrated Cellular Responses Laboratory, Fralin Biomedical Research Institute, Department of Biological Sciences, and Center for Drug Discovery, Virginia Tech, Roanoke, VA, 24016, USA
| | - Anne M Brown
- Research and Informatics, University Libraries, Biochemistry Department, and Center for Drug Discovery, Virginia Tech, Blacksburg, 24061, VA, USA
| | - Daniel G S Capelluto
- Protein Signaling Domains Laboratory, Department of Biological Sciences, Fralin Life Sciences Institute, and Center for Soft Matter and Biological Physics, Virginia Tech, Blacksburg, VA, 24061, USA.
| |
Collapse
|
|
14
|
Disabled-2: a positive regulator of the early differentiation of myoblasts. Cell Tissue Res 2020; 381:493-508. [PMID: 32607799 PMCID: PMC7431403 DOI: 10.1007/s00441-020-03237-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 06/05/2020] [Indexed: 11/25/2022]
Abstract
Dab2 is an adaptor protein and a tumor suppressor. Our previous study has found that Dab2 was expressed in early differentiating skeletal muscles in mouse embryos. In this study, we determined the role of Dab2 in the skeletal muscle differentiation using C2C12 myoblasts in vitro and Xenopus laevis embryos in vivo. The expression of Dab2 was increased in C2C12 myoblasts during the formation of myotubes in vitro. Knockdown of Dab2 expression in C2C12 myoblasts resulted in a reduction of myotube formation, whereas the myotube formation was enhanced upon overexpression of Dab2. Re-expression of Dab2 in C2C12 myoblasts with downregulated expression of Dab2 restored their capacity to form myotubes. Microarray profiling and subsequent network analyses on the 155 differentially expressed genes after Dab2 knockdown showed that Mef2c was an important myogenic transcription factor regulated by Dab2 through the p38 MAPK pathway. It was also involved in other pathways that are associated with muscular development and functions. In Xenopus embryos developed in vivo, XDab2 was expressed in the myotome of somites where various myogenic markers were also expressed. Knockdown of XDab2 expression with antisense morpholinos downregulated the expression of myogenic markers in somites. In conclusion, this study is the first to provide solid evidence to show that Dab2 is a positive regulator of the early myoblast differentiation.
Collapse
|
|
15
|
Jossin Y. Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation. Biomolecules 2020; 10:biom10060964. [PMID: 32604886 PMCID: PMC7355739 DOI: 10.3390/biom10060964] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 06/24/2020] [Accepted: 06/24/2020] [Indexed: 12/14/2022] Open
Abstract
During embryonic development and adulthood, Reelin exerts several important functions in the brain including the regulation of neuronal migration, dendritic growth and branching, dendritic spine formation, synaptogenesis and synaptic plasticity. As a consequence, the Reelin signaling pathway has been associated with several human brain disorders such as lissencephaly, autism, schizophrenia, bipolar disorder, depression, mental retardation, Alzheimer’s disease and epilepsy. Several elements of the signaling pathway are known. Core components, such as the Reelin receptors very low-density lipoprotein receptor (VLDLR) and Apolipoprotein E receptor 2 (ApoER2), Src family kinases Src and Fyn, and the intracellular adaptor Disabled-1 (Dab1), are common to most but not all Reelin functions. Other downstream effectors are, on the other hand, more specific to defined tasks. Reelin is a large extracellular protein, and some aspects of the signal are regulated by its processing into smaller fragments. Rather than being inhibitory, the processing at two major sites seems to be fulfilling important physiological functions. In this review, I describe the various cellular events regulated by Reelin and attempt to explain the current knowledge on the mechanisms of action. After discussing the shared and distinct elements of the Reelin signaling pathway involved in neuronal migration, dendritic growth, spine development and synaptic plasticity, I briefly outline the data revealing the importance of Reelin in human brain disorders.
Collapse
Affiliation(s)
- Yves Jossin
- Laboratory of Mammalian Development & Cell Biology, Institute of Neuroscience, Université Catholique de Louvain, 1200 Brussels, Belgium
| |
Collapse
|
|
16
|
Fyn Tyrosine Kinase as Harmonizing Factor in Neuronal Functions and Dysfunctions. Int J Mol Sci 2020; 21:ijms21124444. [PMID: 32580508 PMCID: PMC7352836 DOI: 10.3390/ijms21124444] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 06/19/2020] [Accepted: 06/20/2020] [Indexed: 12/25/2022] Open
Abstract
Fyn is a non-receptor or cytoplasmatic tyrosine kinase (TK) belonging to the Src family kinases (SFKs) involved in multiple transduction pathways in the central nervous system (CNS) including synaptic transmission, myelination, axon guidance, and oligodendrocyte formation. Almost one hundred years after the original description of Fyn, this protein continues to attract extreme interest because of its multiplicity of actions in the molecular signaling pathways underlying neurodevelopmental as well as neuropathologic events. This review highlights and summarizes the most relevant recent findings pertinent to the role that Fyn exerts in the brain, emphasizing aspects related to neurodevelopment and synaptic plasticity. Fyn is a common factor in healthy and diseased brains that targets different proteins and shapes different transduction signals according to the neurological conditions. We will primarily focus on Fyn-mediated signaling pathways involved in neuronal differentiation and plasticity that have been subjected to considerable attention lately, opening the fascinating scenario to target Fyn TK for the development of potential therapeutic interventions for the treatment of CNS injuries and certain neurodegenerative disorders like Alzheimer’s disease.
Collapse
|
|
17
|
Stefanov A, Novelli E, Strettoi E. Inner retinal preservation in the photoinducible I307N rhodopsin mutant mouse, a model of autosomal dominant retinitis pigmentosa. J Comp Neurol 2019; 528:1502-1522. [PMID: 31811649 PMCID: PMC7187456 DOI: 10.1002/cne.24838] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 12/03/2019] [Accepted: 12/03/2019] [Indexed: 12/20/2022]
Abstract
Rod‐cone degenerations, for example, retinitis pigmentosa are leading causes of blindness worldwide. Despite slow disease progression in humans, vision loss is inevitable; therefore, development of vision restoration strategies is crucial. Among others, promising approaches include optogenetics and prosthetic implants, which aim to bypass lost photoreceptors (PRs). Naturally, the efficacy of these therapeutic strategies will depend on inner retinal structural and functional preservation. The present study shows that in photoinducible I307N rhodopsin mice (Translational Vision Research Model 4 [Tvrm4]), a 12k lux light exposure eliminates PRs in the central retina in 1 week, but interneurons and their synapses are maintained for as long as 9 weeks postinduction. Despite bipolar cell dendritic retraction and moderate loss of horizontal cells, the survival rate of various cell types is very high. Significant preservation of conventional synapses and gap junctions in the inner plexiform layer is also observed. We found the number of synaptic ribbons to gradually decline and their ultrastructure to become transiently abnormal, although based on our findings intrinsic retinal architecture is maintained despite complete loss of PRs. Unlike common rodent models of PR degeneration, where the disease phenotype often interferes with retinal development, in Tvrm4 mice, the degenerative process can be induced after retinal development is complete. This time course more closely mimics the timing of disease onset in affected patients. Stability of the inner retina found in these mutants 2 months after PR degeneration suggests moderate, stereotyped remodeling in the early stages of the human disease and represents a promising finding for prompt approaches of vision restoration.
Collapse
Affiliation(s)
- Antonia Stefanov
- Institute of Neuroscience, Italian National Research Council - CNR, Pisa, Italy.,Regional Doctoral School of Neuroscience, University of Florence, Florence, Italy
| | - Elena Novelli
- Institute of Neuroscience, Italian National Research Council - CNR, Pisa, Italy
| | - Enrica Strettoi
- Institute of Neuroscience, Italian National Research Council - CNR, Pisa, Italy
| |
Collapse
|
|
18
|
Zhang B, Wang W, Zhang Z, Hu Y, Meng F, Wang F, Lou H, Zhu L, Godbout R, Duan S, Gao Z. Alternative Splicing of Disabled-1 Controls Multipolar-to-Bipolar Transition of Migrating Neurons in the Neocortex. Cereb Cortex 2019; 28:3457-3467. [PMID: 28968791 DOI: 10.1093/cercor/bhx212] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 07/24/2017] [Indexed: 11/14/2022] Open
Abstract
Multipolar-to-bipolar transition (MBT) is crucial for the neuronal migration and positioning in the neocortex. Reelin-Disabled-1 (Dab1) signaling plays a pivotal role in neuronal migration, yet how Dab1 coordinatively regulates downstream molecules to affect MBT remains unclear. We have previously found that alternative splicing produces multiple Dab1 isoforms with different tyrosine motifs and differential ability to recruit downstream effectors. Here, we report that splicing of Dab1 exons 7 and 8 and 9bc dynamically regulates the inclusion and activities of Dab1 tyrosine motifs in the neocortex. By in utero electroporation, we show that expression of Dab1 isoforms missing exons 7 and 8 or retaining exons 9bc in WT neurons resulted in neuronal migration defects with attenuated Dab1 tyrosine phosphorylation, disrupted leading process extension, and disorientated multipolar neurons in the multipolar accumulation zone. Introducing the canonical Dab1 form, but not those missing exons 7 and 8 or retaining exons 9bc, into Dab1-deficient neurons promoted MBT and rescued neuronal migration defects, suggesting that alternative splicing of Dab1 modulates the tyrosine motif switch and mediates MBT of cortical neurons. Our study reveals a critical mechanism by which Dab1 alternative splicing coordinately controls MBT and neuronal migration in a spatiotemporal manner.
Collapse
Affiliation(s)
- Bin Zhang
- Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Key Laboratory of Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Weiwei Wang
- Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Key Laboratory of Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhenjie Zhang
- Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Key Laboratory of Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Yaling Hu
- Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Key Laboratory of Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Fan Meng
- Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Key Laboratory of Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Fan Wang
- Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Key Laboratory of Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Huifang Lou
- Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Key Laboratory of Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Liya Zhu
- Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Key Laboratory of Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Roseline Godbout
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Shumin Duan
- Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Key Laboratory of Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhihua Gao
- Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Key Laboratory of Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| |
Collapse
|
|
19
|
Zhang JH, Zhao YF, He XX, Zhao Y, He ZX, Zhang L, Huang Y, Wang YB, Hu L, Liu L, Yu HL, Xu JH, Lai MM, Zhao DD, Cui L, Guo WX, Xiong WC, Ding YQ, Zhu XJ. DCC-Mediated Dab1 Phosphorylation Participates in the Multipolar-to-Bipolar Transition of Migrating Neurons. Cell Rep 2019; 22:3598-3611. [PMID: 29590626 DOI: 10.1016/j.celrep.2018.03.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 02/10/2018] [Accepted: 02/28/2018] [Indexed: 11/25/2022] Open
Abstract
Newborn neurons undergo inside-out migration to their final destinations during neocortical development. Reelin-induced tyrosine phosphorylation of disabled 1 (Dab1) is a critical mechanism controlling cortical neuron migration. However, the roles of Reelin-independent phosphorylation of Dab1 remain unclear. Here, we report that deleted in colorectal carcinoma (DCC) interacts with Dab1 via its P3 domain. Netrin 1, a DCC ligand, induces Dab1 phosphorylation at Y220 and Y232. Interestingly, knockdown of DCC or truncation of its P3 domain dramatically delays neuronal migration and impairs the multipolar-to-bipolar transition of migrating neurons. Notably, the migration delay and morphological transition defects are rescued by the expression of a phospho-mimetic Dab1 or a constitutively active form of Fyn proto-oncogene (Fyn), a member of the Src-family tyrosine kinases that effectively induces Dab1 phosphorylation. Collectively, these findings illustrate a DCC-Dab1 interaction that ensures proper neuronal migration during neocortical development.
Collapse
Affiliation(s)
- Jian-Hua Zhang
- Key Laboratory of Molecular Epigenetics, Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130021, China
| | - Yi-Fei Zhao
- Key Laboratory of Molecular Epigenetics, Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130021, China
| | - Xiao-Xiao He
- Key Laboratory of Molecular Epigenetics, Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130021, China
| | - Yang Zhao
- Key Laboratory of Molecular Epigenetics, Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130021, China
| | - Zi-Xuan He
- Key Laboratory of Molecular Epigenetics, Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130021, China
| | - Lei Zhang
- Key Laboratory of Arrhythmias, Ministry of Education, East Hospital, and Department of Anatomy and Neurobiology, Collaborative Innovation Center for Brain Science, Tongji University School of Medicine, Shanghai 200092, China
| | - Ying Huang
- Key Laboratory of Arrhythmias, Ministry of Education, East Hospital, and Department of Anatomy and Neurobiology, Collaborative Innovation Center for Brain Science, Tongji University School of Medicine, Shanghai 200092, China
| | - Yu-Bing Wang
- Key Laboratory of Arrhythmias, Ministry of Education, East Hospital, and Department of Anatomy and Neurobiology, Collaborative Innovation Center for Brain Science, Tongji University School of Medicine, Shanghai 200092, China
| | - Ling Hu
- Key Laboratory of Arrhythmias, Ministry of Education, East Hospital, and Department of Anatomy and Neurobiology, Collaborative Innovation Center for Brain Science, Tongji University School of Medicine, Shanghai 200092, China
| | - Lin Liu
- Key Laboratory of Molecular Epigenetics, Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130021, China
| | - Hua-Li Yu
- Key Laboratory of Molecular Epigenetics, Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130021, China
| | - Jia-Hui Xu
- Key Laboratory of Molecular Epigenetics, Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130021, China
| | - Ming-Ming Lai
- Key Laboratory of Molecular Epigenetics, Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130021, China
| | - Dong-Dong Zhao
- Key Laboratory of Molecular Epigenetics, Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130021, China
| | - Lei Cui
- Key Laboratory of Molecular Epigenetics, Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130021, China
| | - Wei-Xiang Guo
- State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Wen-Cheng Xiong
- Department of Neurology, Georgia Regents University, Augusta, GA, USA; Department of Neuroscience, School of Medicine, Case Western Reserve University, Cleveland, OH 44120, USA
| | - Yu-Qiang Ding
- Key Laboratory of Arrhythmias, Ministry of Education, East Hospital, and Department of Anatomy and Neurobiology, Collaborative Innovation Center for Brain Science, Tongji University School of Medicine, Shanghai 200092, China; Institute of Brain Sciences, Fudan University, Shanghai 200031, China.
| | - Xiao-Juan Zhu
- Key Laboratory of Molecular Epigenetics, Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130021, China.
| |
Collapse
|
|
20
|
Wang X, Yvone GM, Cilluffo M, Kim AS, Basbaum AI, Phelps PE. Mispositioned Neurokinin-1 Receptor-Expressing Neurons Underlie Heat Hyperalgesia in Disabled-1 Mutant Mice. eNeuro 2019; 6:ENEURO.0131-19.2019. [PMID: 31122949 PMCID: PMC6584071 DOI: 10.1523/eneuro.0131-19.2019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 05/11/2019] [Accepted: 05/15/2019] [Indexed: 11/30/2022] Open
Abstract
Reelin (Reln) and Disabled-1 (Dab1) participate in the Reln-signaling pathway and when either is deleted, mutant mice have the same spinally mediated behavioral abnormalities, increased sensitivity to noxious heat and a profound loss in mechanical sensitivity. Both Reln and Dab1 are highly expressed in dorsal horn areas that receive and convey nociceptive information, Laminae I-II, lateral Lamina V, and the lateral spinal nucleus (LSN). Lamina I contains both projection neurons and interneurons that express Neurokinin-1 receptors (NK1Rs) and they transmit information about noxious heat both within the dorsal horn and to the brain. Here, we ask whether the increased heat nociception in Reln and dab1 mutants is due to incorrectly positioned dorsal horn neurons that express NK1Rs. We found more NK1R-expressing neurons in Reln-/- and dab1-/- Laminae I-II than in their respective wild-type mice, and some NK1R neurons co-expressed Dab1 and the transcription factor Lmx1b, confirming their excitatory phenotype. Importantly, heat stimulation in dab1-/- mice induced Fos in incorrectly positioned NK1R neurons in Laminae I-II. Next, we asked whether these ectopically placed and noxious-heat responsive NK1R neurons participated in pain behavior. Ablation of the superficial NK1Rs with an intrathecal injection of a substance P analog conjugated to the toxin saporin (SSP-SAP) eliminated the thermal hypersensitivity of dab1-/- mice, without altering their mechanical insensitivity. These results suggest that ectopically positioned NK1R-expressing neurons underlie the heat hyperalgesia of Reelin-signaling pathway mutants, but do not contribute to their profound mechanical insensitivity.
Collapse
Affiliation(s)
- Xidao Wang
- Departments of Anatomy and Physiology and W. M. Keck Foundation Center for Integrative Neuroscience, University of California, San Francisco, CA 94158
| | - Griselda M Yvone
- Department of Integrative Biology and Physiology UCLA, Los Angeles, Los Angeles, CA 90095
| | - Marianne Cilluffo
- Department of Integrative Biology and Physiology UCLA, Los Angeles, Los Angeles, CA 90095
| | - Ashley S Kim
- Department of Integrative Biology and Physiology UCLA, Los Angeles, Los Angeles, CA 90095
| | - Allan I Basbaum
- Departments of Anatomy and Physiology and W. M. Keck Foundation Center for Integrative Neuroscience, University of California, San Francisco, CA 94158
| | - Patricia E Phelps
- Department of Integrative Biology and Physiology UCLA, Los Angeles, Los Angeles, CA 90095
| |
Collapse
|
|
21
|
Wang D, Enck J, Howell BW, Olson EC. Ethanol Exposure Transiently Elevates but Persistently Inhibits Tyrosine Kinase Activity and Impairs the Growth of the Nascent Apical Dendrite. Mol Neurobiol 2019; 56:5749-5762. [PMID: 30674037 DOI: 10.1007/s12035-019-1473-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 01/10/2019] [Indexed: 12/11/2022]
Abstract
Dendritogenesis can be impaired by exposure to alcohol, and aspects of this impairment share phenotypic similarities to dendritic defects observed after blockade of the Reelin-Dab1 tyrosine kinase signaling pathway. In this study, we find that 10 min of alcohol exposure (400 mg/dL ethanol) by itself causes an unexpected increase in tyrosine phosphorylation of many proteins including Src and Dab1 that are essential downstream effectors of Reelin signaling. This increase in phosphotyrosine is dose-dependent and blockable by selective inhibitors of Src Family Kinases (SFKs). However, the response is transient, and phosphotyrosine levels return to baseline after 30 min of continuous ethanol exposure, both in vitro and in vivo. During this latter period, Src is inactivated and Reelin application cannot stimulate Dab1 phosphorylation. This suggests that ethanol initially activates but then silences the Reelin-Dab1 signaling pathway by brief activation and then sustained inactivation of SFKs. Time-lapse analyses of dendritic growth dynamics show an overall decrease in growth and branching compared to controls after ethanol-exposure that is similar to that observed with Reelin-deficiency. However, unlike Reelin-signaling disruptions, the dendritic filopodial speeds are decreased after ethanol exposure, and this decrease is associated with sustained dephosphorylation and activation of cofilin, an F-actin severing protein. These findings suggest that persistent Src inactivation coupled to cofilin activation may contribute to the dendritic disruptions observed with fetal alcohol exposure.
Collapse
Affiliation(s)
- Dandan Wang
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, 505 Irving Ave, Syracuse, NY, 13210, USA.,Developmental Exposure to Alcohol Research Center (DEARC), Binghamton University, Binghamton, NY, 13902, USA
| | - Joshua Enck
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, 505 Irving Ave, Syracuse, NY, 13210, USA.,Developmental Exposure to Alcohol Research Center (DEARC), Binghamton University, Binghamton, NY, 13902, USA
| | - Brian W Howell
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, 505 Irving Ave, Syracuse, NY, 13210, USA
| | - Eric C Olson
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, 505 Irving Ave, Syracuse, NY, 13210, USA. .,Developmental Exposure to Alcohol Research Center (DEARC), Binghamton University, Binghamton, NY, 13902, USA.
| |
Collapse
|
|
22
|
Xian X, Pohlkamp T, Durakoglugil MS, Wong CH, Beck JK, Lane-Donovan C, Plattner F, Herz J. Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer's disease. eLife 2018; 7:40048. [PMID: 30375977 PMCID: PMC6261251 DOI: 10.7554/elife.40048] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 10/29/2018] [Indexed: 12/13/2022] Open
Abstract
ApoE4 genotype is the most prevalent and also clinically most important risk factor for late-onset Alzheimer’s disease (AD). Available evidence suggests that the root cause for this increased risk is a trafficking defect at the level of the early endosome. ApoE4 differs from the most common ApoE3 isoform by a single amino acid that increases its isoelectric point and promotes unfolding of ApoE4 upon endosomal vesicle acidification. We found that pharmacological and genetic inhibition of NHE6, the primary proton leak channel in the early endosome, in rodents completely reverses the ApoE4-induced recycling block of the ApoE receptor Apoer2/Lrp8 and the AMPA- and NMDA-type glutamate receptors that are regulated by, and co-endocytosed in a complex with, Apoer2. Moreover, NHE6 inhibition restores the Reelin-mediated modulation of excitatory synapses that is impaired by ApoE4. Our findings suggest a novel potential approach for the prevention of late-onset AD. Alzheimer’s disease is a degenerative condition that destroys connections between brain cells leading to memory loss, confusion and difficulties in thinking. Apolipoprotein E is a protein that carries fatty substances called lipids and cholesterol around the brain, and plays an important role in repair mechanisms. There are three major forms of Apolipoprotein E, and individuals who carry a version known as ApoE4 are up to 10 times more likely to develop Alzheimer’s disease than those who carry other variations. In nerve cells, or neurons, Apolipoprotein E binds to a specific family of receptors. One of these receptors, called Apoer2, is found in the synaptic gap between neurons, where it regulates their activities. Both Apolipoprotein E and Apoer2 are taken into the cell within compartments known as endosomal vesicles. Usually, the Apoer2 receptor is quickly recycled back to the surface of the cell, but this recycling process is delayed in individuals with the ApoE4 version of Apolipoprotein E. Apoer2 is just one of many different receptors on the surface of neurons that are taken into vesicles before being recycled back to the cell surface. The fluid inside these vesicles becomes progressively more acidic as they move through the cell. This process helps to control the interaction of these receptors with their binding partners and to regulate their movement and recycling. Here, Xian, Pohlkamp et al. investigated whether changing the acidity of vesicles in rat neurons could overcome the block in recycling Apoer2 – and other receptors that travel with Apoer2 in the same compartments – in the presence of ApoE4. A protein called NHE6 is embedded in the membrane of vesicles called early endosomes and acts to make the vesicles less acidic. Xian, Pohlkamp et al. used drugs to block the activity of NHE6, which led to the vesicles becoming more acidic and allowed Apoer2 to be recycled faster. Using a genetic approach known as siRNA knockdown to decrease the amount of NHE6 produced in neurons also had a similar effect on Apoer2 recycling. Together these findings suggest that drugs that make vesicles in neurons more acidic may have the potential to help prevent individuals that carry the ApoE4 protein from developing Alzheimer’s disease. Current drugs that target NHE6 also affect other molecules, which can often lead to side effects. A next step will be to develop tailor-made, small molecule drugs that can enter the brain efficiently and selectively block NHE6.
Collapse
Affiliation(s)
- Xunde Xian
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.,Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United States
| | - Theresa Pohlkamp
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.,Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United States
| | - Murat S Durakoglugil
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.,Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United States
| | - Connie H Wong
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.,Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United States
| | | | - Courtney Lane-Donovan
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.,Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United States
| | - Florian Plattner
- Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United States.,Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, United States
| | - Joachim Herz
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.,Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United States.,Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States.,Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, United States
| |
Collapse
|
|
23
|
Dairaghi L, Flannery E, Giacobini P, Saglam A, Saadi H, Constantin S, Casoni F, Howell BW, Wray S. Reelin Can Modulate Migration of Olfactory Ensheathing Cells and Gonadotropin Releasing Hormone Neurons via the Canonical Pathway. Front Cell Neurosci 2018; 12:228. [PMID: 30127721 PMCID: PMC6088185 DOI: 10.3389/fncel.2018.00228] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 07/13/2018] [Indexed: 01/14/2023] Open
Abstract
One key signaling pathway known to influence neuronal migration involves the extracellular matrix protein Reelin. Typically, signaling of Reelin occurs via apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor (VLDLR), and the cytoplasmic adapter protein disabled 1 (Dab1). However, non-canonical Reelin signaling has been reported, though no receptors have yet been identified. Cariboni et al. (2005) indicated Dab1-independent Reelin signaling impacts gonadotropin releasing hormone-1 (GnRH) neuronal migration. GnRH cells are essential for reproduction. Prenatal migration of GnRH neurons from the nasal placode to the forebrain, juxtaposed to olfactory axons and olfactory ensheathing cells (OECs), has been well documented, and it is clear that alterations in migration of these cells can cause delayed or absent puberty. This study was initiated to delineate the non-canonical Reelin signaling pathways used by GnRH neurons. Chronic treatment of nasal explants with CR-50, an antibody known to interfere with Reelin homopolymerization and Dab1 phosphorylation, decreased the distance GnRH neurons and OECs migrated. Normal migration of these two cell types was observed when Reelin was co-applied with CR-50. Immunocytochemistry was performed to determine if OECs might transduce Reelin signals via the canonical pathway, and subsequently indirectly altering GnRH neuronal migration. We show that in mouse: (1) both OECs and GnRH cells express ApoER2, VLDLR and Dab1, and (2) GnRH neurons and OECs show a normal distribution in the brain of two mutant reeler lines. These results indicate that the canonical Reelin pathway is present in GnRH neurons and OECs, but that Reelin is not essential for development of these two systems in vivo.
Collapse
Affiliation(s)
- Leigh Dairaghi
- Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Ellen Flannery
- Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, United States
- Coriell Institute for Medical Research, Camden, NJ, United States
| | - Paolo Giacobini
- Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, United States
- Laboratory of Development and Plasticity of the Neuroendocrine Brain, Jean Pierre Aubert Research Centre, INSERM U1172, Lille, France
| | - Aybike Saglam
- Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Hassan Saadi
- Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Stephanie Constantin
- Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Filippo Casoni
- Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, United States
- Division of Neuroscience, San Raffaele Scientific Institute, Università Vita-Salute San Raffaele, Milan, Italy
| | - Brian W. Howell
- Neuroscience and Physiology, Upstate Medical University, Syracuse, NY, United States
| | - Susan Wray
- Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, United States
| |
Collapse
|
|
24
|
Small and large intestine express a truncated Dab1 isoform that assembles in cell-cell junctions and co-localizes with proteins involved in endocytosis. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2018; 1860:1231-1241. [PMID: 29470947 DOI: 10.1016/j.bbamem.2018.02.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 02/02/2018] [Accepted: 02/14/2018] [Indexed: 12/16/2022]
Abstract
Disabled-1 (Dab1) is an essential intracellular adaptor protein in the reelin pathway. Our previous studies in mice intestine showed that Dab1 transmits the reelin signal to cytosolic signalling pathways. Here, we determine the Dab1 isoform expressed in rodent small and large intestine, its subcellular location and co-localization with clathrin, caveolin-1 and N-Wasp. PCR and sequencing analysis reveal that rodent small and large intestine express a Dab1 isoform that misses three (Y198, Y200 and Y220) of the five tyrosine phosphorylation sites present in brain Dab1 isoform (canonical) and contains nuclear localization and export signals. Western blot assays show that both, crypts, which shelter progenitor cells, and enterocytes express the same Dab1 isoform, suggesting that epithelial cell differentiation does not regulate intestinal generation of alternatively spliced Dab1 variants. They also reveal that the canonical and the intestinal Dab1 isoforms differ in their total degree of phosphorylation. Immunostaining assays show that in enterocytes Dab1 localizes at the apical and lateral membranes, apical vesicles, close to adherens junctions and desmosomes, as well as in the nucleus; co-localizes with clathrin and with N-Wasp but not with caveolin-1, and in Caco-2 cells Dab1 localizes at cell-to-cell junctions by a Ca2+-dependent process. In conclusion, the results indicate that in rodent intestine a truncated Dab1 variant transmits the reelin signal and may play a role in clathrin-mediated apical endocytosis and in the control of cell-to-cell junction assembly. A function of intestinal Dab1 variant as a nucleocytoplasmic shuttling protein is also inferred from its sequence and nuclear location.
Collapse
|
|
25
|
Di Donato V, De Santis F, Albadri S, Auer TO, Duroure K, Charpentier M, Concordet JP, Gebhardt C, Del Bene F. An Attractive Reelin Gradient Establishes Synaptic Lamination in the Vertebrate Visual System. Neuron 2018; 97:1049-1062.e6. [PMID: 29429939 DOI: 10.1016/j.neuron.2018.01.030] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 11/11/2017] [Accepted: 01/11/2018] [Indexed: 10/18/2022]
Abstract
A conserved organizational and functional principle of neural networks is the segregation of axon-dendritic synaptic connections into laminae. Here we report that targeting of synaptic laminae by retinal ganglion cell (RGC) arbors in the vertebrate visual system is regulated by a signaling system relying on target-derived Reelin and VLDLR/Dab1a on the projecting neurons. Furthermore, we find that Reelin is distributed as a gradient on the target tissue and stabilized by heparan sulfate proteoglycans (HSPGs) in the extracellular matrix (ECM). Through genetic manipulations, we show that this Reelin gradient is important for laminar targeting and that it is attractive for RGC axons. Finally, we suggest a comprehensive model of synaptic lamina formation in which attractive Reelin counter-balances repulsive Slit1, thereby guiding RGC axons toward single synaptic laminae. We establish a mechanism that may represent a general principle for neural network assembly in vertebrate species and across different brain areas.
Collapse
Affiliation(s)
- Vincenzo Di Donato
- Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215, UPMC Paris-Sorbonne, Paris 75005, France
| | - Flavia De Santis
- Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215, UPMC Paris-Sorbonne, Paris 75005, France
| | - Shahad Albadri
- Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215, UPMC Paris-Sorbonne, Paris 75005, France
| | - Thomas Oliver Auer
- Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215, UPMC Paris-Sorbonne, Paris 75005, France
| | - Karine Duroure
- Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215, UPMC Paris-Sorbonne, Paris 75005, France
| | - Marine Charpentier
- Muséum National d'Histoire Naturelle, INSERM U1154, CNRS UMR7196, Paris 75231, France
| | - Jean-Paul Concordet
- Muséum National d'Histoire Naturelle, INSERM U1154, CNRS UMR7196, Paris 75231, France
| | - Christoph Gebhardt
- Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215, UPMC Paris-Sorbonne, Paris 75005, France.
| | - Filippo Del Bene
- Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215, UPMC Paris-Sorbonne, Paris 75005, France.
| |
Collapse
|
|
26
|
Lutz D, Sharaf A, Drexler D, Kataria H, Wolters-Eisfeld G, Brunne B, Kleene R, Loers G, Frotscher M, Schachner M. Proteolytic cleavage of transmembrane cell adhesion molecule L1 by extracellular matrix molecule Reelin is important for mouse brain development. Sci Rep 2017; 7:15268. [PMID: 29127326 PMCID: PMC5681625 DOI: 10.1038/s41598-017-15311-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Accepted: 10/25/2017] [Indexed: 02/05/2023] Open
Abstract
The cell adhesion molecule L1 and the extracellular matrix protein Reelin play crucial roles in the developing nervous system. Reelin is known to activate signalling cascades regulating neuronal migration by binding to lipoprotein receptors. However, the interaction of Reelin with adhesion molecules, such as L1, has remained poorly explored. Here, we report that full-length Reelin and its N-terminal fragments N-R2 and N-R6 bind to L1 and that full-length Reelin and its N-terminal fragment N-R6 proteolytically cleave L1 to generate an L1 fragment with a molecular mass of 80 kDa (L1-80). Expression of N-R6 and generation of L1-80 coincide in time at early developmental stages of the cerebral cortex. Reelin-mediated generation of L1-80 is involved in neurite outgrowth and in stimulation of migration of cultured cortical and cerebellar neurons. Morphological abnormalities in layer formation of the cerebral cortex of L1-deficient mice partially overlap with those of Reelin-deficient reeler mice. In utero electroporation of L1-80 into reeler embryos normalised the migration of cortical neurons in reeler embryos. The combined results indicate that the direct interaction between L1 and Reelin as well as the Reelin-mediated generation of L1-80 contribute to brain development at early developmental stages.
Collapse
Affiliation(s)
- David Lutz
- Institute for Structural Neurobiology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany. .,Institute for Biosynthesis of Neural Structures, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
| | - Ahmed Sharaf
- Institute for Structural Neurobiology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Dagmar Drexler
- Institute for Structural Neurobiology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Hardeep Kataria
- Institute for Biosynthesis of Neural Structures, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Gerrit Wolters-Eisfeld
- Institute for Biosynthesis of Neural Structures, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Bianka Brunne
- Institute for Structural Neurobiology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Ralf Kleene
- Institute for Biosynthesis of Neural Structures, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Gabriele Loers
- Institute for Biosynthesis of Neural Structures, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Michael Frotscher
- Institute for Structural Neurobiology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
| | - Melitta Schachner
- Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, 604 Allison Road, Piscataway, NJ, 08854, USA. .,Center for Neuroscience, Shantou University Medical College, 22 Xin Ling Road, Shantou, Guandong, 515041, China.
| |
Collapse
|
|
27
|
Finkielstein CV, Capelluto DGS. Disabled-2: A modular scaffold protein with multifaceted functions in signaling. Bioessays 2017; 38 Suppl 1:S45-55. [PMID: 27417122 DOI: 10.1002/bies.201670907] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 07/08/2015] [Accepted: 07/12/2015] [Indexed: 12/14/2022]
Abstract
Disabled-2 (Dab2) is a multimodular scaffold protein with signaling roles in the domains of cell growth, trafficking, differentiation, and homeostasis. Emerging evidences place Dab2 as a novel modulator of cell-cell interaction; however, its mode of action has remained largely elusive. In this review, we highlight the relevance of Dab2 function in cell signaling and development and provide the most recent and comprehensive analysis of Dab2's action as a mediator of homotypical and heterotypical interactions. Accordingly, Dab-2 controls the extent of platelet aggregation through various motifs within its N-terminus. Dab2 interacts with the cytosolic tail of the integrin receptor blocking inside-out signaling, whereas extracellular Dab2 competes with fibrinogen for integrin αIIb β3 receptor binding and, thus, modulates outside-in signaling. An additional level of regulation results from Dab2's association with cell surface lipids, an event that defines the extent of cell-cell interactions. As a multifaceted regulator, Dab2 acts as a mediator of endocytosis through its association with the [FY]xNPx[YF] motifs of internalized cell surface receptors, phosphoinositides, and clathrin. Other emerging roles of Dab2 include its participation in developmental mechanisms required for tissue formation and in modulation of immune responses. This review highlights the various novel mechanisms by which Dab2 mediates an array of signaling events with vast physiological consequences.
Collapse
Affiliation(s)
- Carla V Finkielstein
- Integrated Cellular Responses Laboratory, Department of Biological Sciences, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, VA, USA
| | - Daniel G S Capelluto
- Protein Signaling Domains Laboratory, Department of Biological Sciences, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, VA, USA
| |
Collapse
|
|
28
|
C-Terminal Region Truncation of RELN Disrupts an Interaction with VLDLR, Causing Abnormal Development of the Cerebral Cortex and Hippocampus. J Neurosci 2017; 37:960-971. [PMID: 28123028 DOI: 10.1523/jneurosci.1826-16.2016] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Revised: 11/03/2016] [Accepted: 11/19/2016] [Indexed: 11/21/2022] Open
Abstract
We discovered a hypomorphic reelin (Reln) mutant with abnormal cortical lamination and no cerebellar hypoplasia. This mutant, RelnCTRdel, carries a chemically induced splice-site mutation that truncates the C-terminal region (CTR) domain of RELN protein and displays remarkably distinct phenotypes from reeler The mutant does not have an inverted cortex, but cortical neurons overmigrate and invade the marginal zone, which are characteristics similar to a phenotype seen in the cerebral cortex of Vldlrnull mice. The dentate gyrus shows a novel phenotype: the infrapyramidal blade is absent, while the suprapyramidal blade is present and laminated. Genetic epistasis analysis showed that RelnCTRdel/Apoer2null double homozygotes have phenotypes akin to those of reeler mutants, while RelnCTRdel/Vldlrnull mice do not. Given that the receptor double knock-out mice resemble reeler mutants, we infer that RelnCTRdel/Apoer2null double homozygotes have both receptor pathways disrupted. This suggests that CTR-truncation disrupts an interaction with VLDLR (very low-density lipoprotein receptor), while the APOER2 signaling pathway remains active, which accounts for the hypomorphic phenotype in RelnCTRdel mice. A RELN-binding assay confirms that CTR truncation significantly decreases RELN binding to VLDLR, but not to APOER2. Together, the in vitro and in vivo results demonstrate that the CTR domain confers receptor-binding specificity of RELN. SIGNIFICANCE STATEMENT Reelin signaling is important for brain development and is associated with human type II lissencephaly. Reln mutations in mice and humans are usually associated with cerebellar hypoplasia. A new Reln mutant with a truncation of the C-terminal region (CTR) domain shows that Reln mutation can cause abnormal phenotypes in the cortex and hippocampus without cerebellar hypoplasia. Genetic analysis suggested that CTR truncation disrupts an interaction with the RELN receptor VLDLR (very low-density lipoprotein receptor); this was confirmed by a RELN-binding assay. This result provides a mechanistic explanation for the hypomorphic phenotype of the CTR-deletion mutant, and further suggests that Reln mutations may cause more subtle forms of human brain malformation than classic lissencephalies.
Collapse
|
|
29
|
Seixas AI, Loureiro JR, Costa C, Ordóñez-Ugalde A, Marcelino H, Oliveira CL, Loureiro JL, Dhingra A, Brandão E, Cruz VT, Timóteo A, Quintáns B, Rouleau GA, Rizzu P, Carracedo Á, Bessa J, Heutink P, Sequeiros J, Sobrido MJ, Coutinho P, Silveira I. A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia. Am J Hum Genet 2017; 101:87-103. [PMID: 28686858 DOI: 10.1016/j.ajhg.2017.06.007] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 06/13/2017] [Indexed: 01/01/2023] Open
Abstract
Advances in human genetics in recent years have largely been driven by next-generation sequencing (NGS); however, the discovery of disease-related gene mutations has been biased toward the exome because the large and very repetitive regions that characterize the non-coding genome remain difficult to reach by that technology. For autosomal-dominant spinocerebellar ataxias (SCAs), 28 genes have been identified, but only five SCAs originate from non-coding mutations. Over half of SCA-affected families, however, remain without a genetic diagnosis. We used genome-wide linkage analysis, NGS, and repeat analysis to identify an (ATTTC)n insertion in a polymorphic ATTTT repeat in DAB1 in chromosomal region 1p32.2 as the cause of autosomal-dominant SCA; this region has been previously linked to SCA37. The non-pathogenic and pathogenic alleles have the configurations [(ATTTT)7-400] and [(ATTTT)60-79(ATTTC)31-75(ATTTT)58-90], respectively. (ATTTC)n insertions are present on a distinct haplotype and show an inverse correlation between size and age of onset. In the DAB1-oriented strand, (ATTTC)n is located in 5' UTR introns of cerebellar-specific transcripts arising mostly during human fetal brain development from the usage of alternative promoters, but it is maintained in the adult cerebellum. Overexpression of the transfected (ATTTC)58 insertion, but not (ATTTT)n, leads to abnormal nuclear RNA accumulation. Zebrafish embryos injected with RNA of the (AUUUC)58 insertion, but not (AUUUU)n, showed lethal developmental malformations. Together, these results establish an unstable repeat insertion in DAB1 as a cause of cerebellar degeneration; on the basis of the genetic and phenotypic evidence, we propose this mutation as the molecular basis for SCA37.
Collapse
|
|
30
|
Kannan R, Giniger E. New perspectives on the roles of Abl tyrosine kinase in axon patterning. Fly (Austin) 2017; 11:260-270. [PMID: 28481649 DOI: 10.1080/19336934.2017.1327106] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
The Abelson tyrosine kinase (Abl) lies at the heart of one of the small set of ubiquitous, conserved signal transduction pathways that do much of the work of development and physiology. Abl signaling is essential to epithelial integrity, motility of autonomous cells such as blood cells, and axon growth and guidance in the nervous system. However, though Abl was one of the first of these conserved signaling machines to be identified, it has been among the last to have its essential architecture elucidated. Here we will first discuss some of the challenges that long delayed the dissection of this pathway, and what they tell us about the special problems of investigating dynamic processes like motility. We will then describe our recent experiments that revealed the functional organization of the Abl pathway in Drosophila neurons. Finally, in the second part of the review we will introduce a different kind of complexity in the role of Abl in motility: the discovery of a previously unappreciated function in protein secretion and trafficking. We will provide evidence that the secretory function of Abl also contributes to its role in axon growth and guidance, and finally end with a discussion of the challenges that Abl pleiotropy provide for the investigator, but the opportunities that it provides for coordinating biological regulation.
Collapse
Affiliation(s)
- Ramakrishnan Kannan
- a Neurobiology Research Center (NRC), Department of Psychiatry , National Institute of Mental Health and Neurosciences , Bangalore , India
| | - Edward Giniger
- b National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda , MD
| |
Collapse
|
|
31
|
Kannan R, Song JK, Karpova T, Clarke A, Shivalkar M, Wang B, Kotlyanskaya L, Kuzina I, Gu Q, Giniger E. The Abl pathway bifurcates to balance Enabled and Rac signaling in axon patterning in Drosophila. Development 2017; 144:487-498. [PMID: 28087633 DOI: 10.1242/dev.143776] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Accepted: 12/15/2016] [Indexed: 01/31/2023]
Abstract
The Abl tyrosine kinase signaling network controls cell migration, epithelial organization, axon patterning and other aspects of development. Although individual components are known, the relationships among them remain unresolved. We now use FRET measurements of pathway activity, analysis of protein localization and genetic epistasis to dissect the structure of this network in Drosophila We find that the adaptor protein Disabled stimulates Abl kinase activity. Abl suppresses the actin-regulatory factor Enabled, and we find that Abl also acts through the GEF Trio to stimulate the signaling activity of Rac GTPase: Abl gates the activity of the spectrin repeats of Trio, allowing them to relieve intramolecular repression of Trio GEF activity by the Trio N-terminal domain. Finally, we show that a key target of Abl signaling in axons is the WAVE complex that promotes the formation of branched actin networks. Thus, we show that Abl constitutes a bifurcating network, suppressing Ena activity in parallel with stimulation of WAVE. We suggest that the balancing of linear and branched actin networks by Abl is likely to be central to its regulation of axon patterning.
Collapse
Affiliation(s)
- Ramakrishnan Kannan
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jeong-Kuen Song
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| | - Tatiana Karpova
- National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Akanni Clarke
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| | - Madhuri Shivalkar
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| | - Benjamin Wang
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| | - Lyudmila Kotlyanskaya
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| | - Irina Kuzina
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| | - Qun Gu
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| | - Edward Giniger
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| |
Collapse
|
|
32
|
Early Purkinje Cell Development and the Origins of Cerebellar Patterning. CONTEMPORARY CLINICAL NEUROSCIENCE 2017. [DOI: 10.1007/978-3-319-59749-2_4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/14/2023]
|
|
33
|
Abstract
Thyroid hormone is a crucial regulator of gene expression in the developing and adult retina. Here we sought to map sites of thyroid hormone signaling at the cellular level using the transgenic FINDT3 reporter mouse model in which neurons express β-galactosidase (β-gal) under the control of a hybrid Gal4-TRα receptor when triiodothyronine (T3) and cofactors of thyroid receptor signaling are present. In the adult retina, nearly all neurons of the ganglion cell layer (GCL, ganglion cells and displaced amacrine cells) showed strong β-gal labeling. In the inner nuclear layer (INL), a minority of glycineric and GABAergic amacrine cells showed β-gal labeling, whereas the majority of amacrine cells were unlabeled. At the level of amacrine types, β-gal labeling was found in a large proportion of the glycinergic AII amacrines, but only in a small proportion of the cholinergic/GABAergic 'starburst' amacrines. At postnatal day 10, there also was a high density of strongly β-gal-labeled neurons in the GCL, but only few amacrine cells were labeled in the INL. There was no labeling of bipolar cells, horizontal cells and Müller glia cells at both stages. Most surprisingly, the photoreceptor somata in the outer nuclear layer also showed no β-gal label, although thyroid hormone is known to control cone opsin expression. This is the first record of thyroid hormone signaling in the inner retina of an adult mammal. We hypothesize that T3 levels in photoreceptors are below the detection threshold of the reporter system. The topographical distribution of β-gal-positive cells in the GCL follows the overall neuron distribution in that layer, with more T3-signaling cells in the ventral than the dorsal half-retina.
Collapse
|
|
34
|
Chai X, Frotscher M. How does Reelin signaling regulate the neuronal cytoskeleton during migration? NEUROGENESIS 2016; 3:e1242455. [PMID: 28265585 DOI: 10.1080/23262133.2016.1242455] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 09/15/2016] [Accepted: 09/25/2016] [Indexed: 01/17/2023]
Abstract
Neuronal migration is an essential step in the formation of laminated brain structures. In the developing cerebral cortex, pyramidal neurons migrate toward the Reelin-containing marginal zone. Reelin is an extracellular matrix protein synthesized by Cajal-Retzius cells. In this review, we summarize our recent results and hypotheses on how Reelin might regulate neuronal migration by acting on the actin and microtubule cytoskeleton. By binding to ApoER2 receptors on the migrating neurons, Reelin induces stabilization of the leading processes extending toward the marginal zone, which involves Dab1 phosphorylation, adhesion molecule expression, cofilin phosphorylation and inhibition of tau phosphorylation. By binding to VLDLR and integrin receptors, Reelin interacts with Lis1 and induces nuclear translocation, accompanied by the ubiquitination of phosphorylated Dab1. Eventually Reelin induces clustering of its receptors resulting in the endocytosis of a Reelin/receptor complex (particularly VLDLR). The resulting decrease in Reelin contributes to neuronal arrest at the marginal zone.
Collapse
Affiliation(s)
- Xuejun Chai
- Institute for Structural Neurobiology, Center for Molecular Neurobiology Hamburg (ZMNH) , Hamburg, Germany
| | - Michael Frotscher
- Institute for Structural Neurobiology, Center for Molecular Neurobiology Hamburg (ZMNH) , Hamburg, Germany
| |
Collapse
|
|
35
|
Lee GH, D'Arcangelo G. New Insights into Reelin-Mediated Signaling Pathways. Front Cell Neurosci 2016; 10:122. [PMID: 27242434 PMCID: PMC4860420 DOI: 10.3389/fncel.2016.00122] [Citation(s) in RCA: 118] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Accepted: 04/27/2016] [Indexed: 11/21/2022] Open
Abstract
Reelin, a multifunctional extracellular protein that is important for mammalian brain development and function, is secreted by different cell types in the prenatal or postnatal brain. The spatiotemporal regulation of Reelin expression and distribution during development relates to its multifaceted function in the brain. Prenatally Reelin controls neuronal radial migration and proper positioning in cortical layers, whereas postnatally Reelin promotes neuronal maturation, synaptic formation and plasticity. The molecular mechanisms underlying the distinct biological functions of Reelin during and after brain development involve unique and overlapping signaling pathways that are activated following Reelin binding to its cell surface receptors. Distinct Reelin ligand isoforms, such as the full-length protein or fragments generated by proteolytic cleavage differentially affect the activity of downstream signaling pathways. In this review, we discuss recent advances in our understanding of the signaling transduction pathways activated by Reelin that regulate different aspects of brain development and function. A core signaling machinery, including ApoER2/VLDLR receptors, Src/Fyn kinases, and the adaptor protein Dab1, participates in all known aspects of Reelin biology. However, distinct downstream mechanisms, such as the Crk/Rap1 pathway and cell adhesion molecules, play crucial roles in the control of neuronal migration, whereas the PI3K/Akt/mTOR pathway appears to be more important for dendrite and spine development. Finally, the NMDA receptor (NMDAR) and an unidentified receptor contribute to the activation of the MEK/Erk1/2 pathway leading to the upregulation of genes involved in synaptic plasticity and learning. This knowledge may provide new insight into neurodevelopmental or neurodegenerative disorders that are associated with Reelin dysfunction.
Collapse
Affiliation(s)
- Gum Hwa Lee
- College of Pharmacy, Chosun University Gwangju, South Korea
| | - Gabriella D'Arcangelo
- Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey Piscataway, NJ, USA
| |
Collapse
|
|
36
|
Lussier AL, Weeber EJ, Rebeck GW. Reelin Proteolysis Affects Signaling Related to Normal Synapse Function and Neurodegeneration. Front Cell Neurosci 2016; 10:75. [PMID: 27065802 PMCID: PMC4809875 DOI: 10.3389/fncel.2016.00075] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 03/11/2016] [Indexed: 01/13/2023] Open
Abstract
Reelin is a neurodevelopmental protein important in adult synaptic plasticity and learning and memory. Recent evidence points to the importance for Reelin proteolysis in normal signaling and in cognitive function. Support for the dysfunction of Reelin proteolysis in neurodegeneration and cognitive dysfunction comes from postmortem analysis of Alzheimer’s diseases (AD) tissues including cerebral spinal fluid (CSF), showing that levels of Reelin fragments are altered in AD compared to control. Potential key proteases involved in Reelin proteolysis have recently been defined, identifying processes that could be altered in neurodegeneration. Introduction of full-length Reelin and its proteolytic fragments into several mouse models of neurodegeneration and neuropsychiatric disorders quickly promote learning and memory. These findings support a role for Reelin in learning and memory and suggest further understanding of these processes are important to harness the potential of this pathway in treating cognitive symptoms in neuropsychiatric and neurodegenerative diseases.
Collapse
Affiliation(s)
- April L Lussier
- Department of Molecular Pharmacology and Physiology, USF Health Byrd Alzheimer's Disease Institute, University of South Florida Tampa, FL, USA
| | - Edwin J Weeber
- Department of Molecular Pharmacology and Physiology, USF Health Byrd Alzheimer's Disease Institute, University of South Florida Tampa, FL, USA
| | - G William Rebeck
- Department of Neuroscience, Georgetown University Washington, DC, USA
| |
Collapse
|
|
37
|
Korn MJ, Mandle QJ, Parent JM. Conditional Disabled-1 Deletion in Mice Alters Hippocampal Neurogenesis and Reduces Seizure Threshold. Front Neurosci 2016; 10:63. [PMID: 26941603 PMCID: PMC4766299 DOI: 10.3389/fnins.2016.00063] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 02/10/2016] [Indexed: 11/13/2022] Open
Abstract
Many animal models of temporal lobe epilepsy (TLE) exhibit altered neurogenesis arising from progenitors within the dentate gyrus subgranular zone (SGZ). Aberrant integration of new neurons into the existing circuit is thought to contribute to epileptogenesis. In particular, adult-born neurons that exhibit ectopic migration and hilar basal dendrites (HBDs) are suggested to be pro-epileptogenic. Loss of reelin signaling may contribute to these morphological changes in patients with epilepsy. We previously demonstrated that conditional deletion of the reelin adaptor protein, disabled-1 (Dab1), from postnatal mouse SGZ progenitors generated dentate granule cells (DGCs) with abnormal dendritic development and ectopic placement. To determine whether the early postnatal loss of reelin signaling is epileptogenic, we conditionally deleted Dab1 in neural progenitors and their progeny on postnatal days 7–8 and performed chronic video-EEG recordings 8–10 weeks later. Dab1-deficient mice did not have spontaneous seizures but exhibited interictal epileptiform abnormalities and a significantly reduced latency to pilocarpine-induced status epilepticus. After chemoconvulsant treatment, over 90% of mice deficient for Dab1 developed generalized motor convulsions with tonic-clonic movements, rearing, and falling compared to <20% of wild-type mice. Recombination efficiency, measured by Cre reporter expression, inversely correlated with time to the first sustained seizure. These pro-epileptogenic changes were associated with decreased neurogenesis and increased numbers of hilar ectopic DGCs. Interestingly, neurons co-expressing the Cre reporter comprised a fraction of these hilar ectopic DGCs cells, suggesting a non-cell autonomous effect for the loss of reelin signaling. We also noted a dispersion of the CA1 pyramidal layer, likely due to hypomorphic effects of the conditional Dab1 allele, but this abnormality did not correlate with seizure susceptibility. These findings suggest that the misplacement or reduction of postnatally-generated DGCs contributes to aberrant circuit development and hyperexcitability, but aberrant neurogenesis after conditional Dab1 deletion alone is not sufficient to produce spontaneous seizures.
Collapse
Affiliation(s)
- Matthew J Korn
- Department of Neurology, University of Michigan Medical Center Ann Arbor, MI, USA
| | - Quinton J Mandle
- Department of Neurology, University of Michigan Medical Center Ann Arbor, MI, USA
| | - Jack M Parent
- Department of Neurology, University of Michigan Medical CenterAnn Arbor, MI, USA; VA Ann Arbor Healthcare SystemAnn Arbor, MI, USA
| |
Collapse
|
|
38
|
Hethorn WR, Ciarlone SL, Filonova I, Rogers JT, Aguirre D, Ramirez RA, Grieco JC, Peters MM, Gulick D, Anderson AE, L Banko J, Lussier AL, Weeber EJ. Reelin supplementation recovers synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome. Eur J Neurosci 2015; 41:1372-80. [PMID: 25864922 PMCID: PMC4676289 DOI: 10.1111/ejn.12893] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Revised: 03/09/2015] [Accepted: 03/12/2015] [Indexed: 01/21/2023]
Abstract
The Reelin signaling pathway is implicated in processes controlling synaptic plasticity and hippocampus-dependent learning and memory. A single direct in vivo application of Reelin enhances long-term potentiation, increases dendritic spine density and improves associative and spatial learning and memory. Angelman syndrome (AS) is a neurological disorder that presents with an overall defect in synaptic function, including decreased long-term potentiation, reduced dendritic spine density, and deficits in learning and memory, making it an attractive model in which to examine the ability of Reelin to recover synaptic function and cognitive deficits. In this study, we investigated the effects of Reelin administration on synaptic plasticity and cognitive function in a mouse model of AS and demonstrated that bilateral, intraventricular injections of Reelin recover synaptic function and corresponding hippocampus-dependent associative and spatial learning and memory. Additionally, we describe alteration of the Reelin profile in tissue from both the AS mouse and post-mortem human brain.
Collapse
Affiliation(s)
- Whitney R Hethorn
- USF Health Byrd Alzheimer's Institute, 4001 East Fletcher Avenue, Tampa, FL, 33613, USA.,Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA
| | - Stephanie L Ciarlone
- USF Health Byrd Alzheimer's Institute, 4001 East Fletcher Avenue, Tampa, FL, 33613, USA.,Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA
| | - Irina Filonova
- USF Health Byrd Alzheimer's Institute, 4001 East Fletcher Avenue, Tampa, FL, 33613, USA.,Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA
| | - Justin T Rogers
- USF Health Byrd Alzheimer's Institute, 4001 East Fletcher Avenue, Tampa, FL, 33613, USA.,Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA
| | - Daniela Aguirre
- Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA
| | - Raquel A Ramirez
- USF Health Byrd Alzheimer's Institute, 4001 East Fletcher Avenue, Tampa, FL, 33613, USA.,Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA
| | - Joseph C Grieco
- USF Health Byrd Alzheimer's Institute, 4001 East Fletcher Avenue, Tampa, FL, 33613, USA.,Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA
| | - Melinda M Peters
- USF Health Byrd Alzheimer's Institute, 4001 East Fletcher Avenue, Tampa, FL, 33613, USA.,Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA
| | - Danielle Gulick
- USF Health Byrd Alzheimer's Institute, 4001 East Fletcher Avenue, Tampa, FL, 33613, USA.,Department of Molecular Medicine, University of South Florida, Tampa, FL, USA
| | - Anne E Anderson
- Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - Jessica L Banko
- USF Health Byrd Alzheimer's Institute, 4001 East Fletcher Avenue, Tampa, FL, 33613, USA.,Department of Molecular Medicine, University of South Florida, Tampa, FL, USA
| | - April L Lussier
- USF Health Byrd Alzheimer's Institute, 4001 East Fletcher Avenue, Tampa, FL, 33613, USA.,Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA
| | - Edwin J Weeber
- USF Health Byrd Alzheimer's Institute, 4001 East Fletcher Avenue, Tampa, FL, 33613, USA.,Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA
| |
Collapse
|
|
39
|
Yap CC, Winckler B. Adapting for endocytosis: roles for endocytic sorting adaptors in directing neural development. Front Cell Neurosci 2015; 9:119. [PMID: 25904845 PMCID: PMC4389405 DOI: 10.3389/fncel.2015.00119] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2015] [Accepted: 03/16/2015] [Indexed: 01/01/2023] Open
Abstract
Proper cortical development depends on the orchestrated actions of a multitude of guidance receptors and adhesion molecules and their downstream signaling. The levels of these receptors on the surface and their precise locations can greatly affect guidance outcomes. Trafficking of receptors to a particular surface locale and removal by endocytosis thus feed crucially into the final guidance outcomes. In addition, endocytosis of receptors can affect downstream signaling (both quantitatively and qualitatively) and regulated endocytosis of guidance receptors is thus an important component of ensuring proper neural development. We will discuss the cell biology of regulated endocytosis and the impact on neural development. We focus our discussion on endocytic accessory proteins (EAPs) (such as numb and disabled) and how they regulate endocytosis and subsequent post-endocytic trafficking of their cognate receptors (such as Notch, TrkB, β-APP, VLDLR, and ApoER2).
Collapse
Affiliation(s)
- Chan Choo Yap
- Department of Neuroscience, University of Virginia Charlottesville, VA, USA
| | - Bettina Winckler
- Department of Neuroscience, University of Virginia Charlottesville, VA, USA
| |
Collapse
|
|
40
|
Wang JT, Song LZ, Li LL, Zhang W, Chai XJ, An L, Chen SL, Frotscher M, Zhao ST. Src controls neuronal migration by regulating the activity of FAK and cofilin. Neuroscience 2015; 292:90-100. [PMID: 25711940 DOI: 10.1016/j.neuroscience.2015.02.025] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 02/12/2015] [Accepted: 02/13/2015] [Indexed: 01/30/2023]
Abstract
Migration of postmitotic neurons in the developing cortex along radial glial fiber is essential for the formation of cortical layers. Several neurological diseases are caused by defects in neuronal migration, underlining the importance of this process for brain function. Multiple molecules are involved in this process. However, the precise mechanisms are largely unknown. In the present study, we examined the expression of Src in the developing cortex and investigated the role of Src in neuronal migration and its cellular and molecular mechanisms. Our results showed that Src was strongly expressed in the cerebral cortex during corticogenesis and mainly targeted to the leading processes of migrating neurons. Overexpression of wildtype Src (Src-WT) and its mutants, constitutively active Src (Src-CA) and dominant negative Src (Src-DN) in the mouse brain by in utero electroporation perturbed neuronal migration through affecting the adhesion properties and cytoskeletal dynamics of migrating neurons. Overexpression of Src-WT and Src-CA induced aggregation and branching of migrating neurons, whereas overexpression of Src-DN led to abnormal elongation of the leading processes of migrating neurons. Furthermore, we showed that Src activates the focal adhesion kinase (FAK) and cofilin by regulating their phosphorylation levels. We conclude that Src controls neuronal migration by regulating adhesion properties and F-actin dynamics of migrating neurons.
Collapse
Affiliation(s)
- J T Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, PR China
| | - L Z Song
- College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, PR China
| | - L L Li
- College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, PR China
| | - W Zhang
- College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, PR China
| | - X J Chai
- Institute for Structural Neurobiology, Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - L An
- College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, PR China
| | - S L Chen
- College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, PR China
| | - M Frotscher
- Institute for Structural Neurobiology, Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - S T Zhao
- College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, PR China.
| |
Collapse
|
|
41
|
Abstract
Members of the low-density lipoprotein (LDL) receptor gene family have a diverse set of biological functions that transcend lipid metabolism. Lipoprotein receptors have broad effects in both the developing and adult brain and participate in synapse development, cargo trafficking, and signal transduction. In addition, several family members play key roles in Alzheimer's disease (AD) pathogenesis and neurodegeneration. This Review summarizes our current understanding of the role lipoprotein receptors play in CNS function and AD pathology, with a special emphasis on amyloid-independent roles in endocytosis and synaptic dysfunction.
Collapse
|
|
42
|
Sonoshita M, Itatani Y, Kakizaki F, Sakimura K, Terashima T, Katsuyama Y, Sakai Y, Taketo MM. Promotion of colorectal cancer invasion and metastasis through activation of NOTCH-DAB1-ABL-RHOGEF protein TRIO. Cancer Discov 2014; 5:198-211. [PMID: 25432929 DOI: 10.1158/2159-8290.cd-14-0595] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
UNLABELLED We have recently identified a metastasis suppressor gene for colorectal cancer: AES/Aes, which encodes an endogenous inhibitor of NOTCH signaling. When Aes is knocked out in the adenomatous epithelium of intestinal polyposis mice, their tumors become malignant, showing marked submucosal invasion and intravasation. Here, we show that one of the genes induced by NOTCH signaling in colorectal cancer is DAB1/Dab1. Genetic depletion of DAB1 suppresses cancer invasion and metastasis in the NOTCH signaling-activated mice. DAB1 is phosphorylated by ABL tyrosine kinase, which activates ABL reciprocally. Consistently, inhibition of ABL suppresses cancer invasion in mice. Furthermore, we show that one of the targets of ABL is the RAC/RHOGEF protein TRIO, and that phosphorylation at its Tyr residue 2681 (pY2681) causes RHO activation in colorectal cancer cells. Its unphosphorylatable mutation TRIO Y2681F reduces RHOGEF activity and inhibits invasion of colorectal cancer cells. Importantly, TRIO pY2681 correlates with significantly poorer prognosis of patients with colorectal cancer after surgery. SIGNIFICANCE These results indicate that TRIO pY2681 is one of the downstream effectors of NOTCH signaling activation in colorectal cancer, and can be a prognostic marker, helping to determine the therapeutic modality of patients with colorectal cancer.
Collapse
Affiliation(s)
- Masahiro Sonoshita
- Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshiro Itatani
- Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Fumihiko Kakizaki
- Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kenji Sakimura
- Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Toshio Terashima
- Department of Physiology and Cell Biology, Division of Anatomy and Neurobiology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yu Katsuyama
- Division of Developmental Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshiharu Sakai
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - M Mark Taketo
- Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
| |
Collapse
|
|
43
|
Burrell TC, Divekar SD, Weeber EJ, Rebeck GW. Fyn tyrosine kinase increases Apolipoprotein E Receptor 2 levels and phosphorylation. PLoS One 2014; 9:e110845. [PMID: 25340851 PMCID: PMC4207760 DOI: 10.1371/journal.pone.0110845] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Accepted: 09/25/2014] [Indexed: 11/27/2022] Open
Abstract
Apolipoprotein E Receptor 2 (ApoER2) and the tyrosine kinase Fyn are both members of the Reelin pathway, a signaling pathway essential for the laminar formation of the cortex during development and proper dendritic spine density and long-term potential (LTP) in the adult brain. In the presence of extracellular Reelin, ApoER2 binds the intracellular protein Dab1, an adaptor protein that is phosphorylated by Fyn. However, direct interactions between ApoER2 and Fyn are not well defined. Here, we show that total levels of ApoER2 and surface levels of ApoER2 are increased by active Fyn. Via a separate mechanism, ApoER2 is also phosphorylated by Fyn, an event that peaks in the postnatal cortex at day 5 and can occur at multiple ApoER2 tyrosine residues. Dab1 is also involved in this phosphorylation, promoting the phosphorylation of ApoER2 by Fyn when it is itself phosphorylated. These results elucidate some of the intracellular mechanisms that give rise to a functional Reelin pathway.
Collapse
Affiliation(s)
- Teal C. Burrell
- Department of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia, United States of America
| | - Shailaja D. Divekar
- Department of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia, United States of America
| | - Edwin J. Weeber
- Department of Molecular Pharmacology and Physiology, University of South Florida Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, Florida, United States of America
| | - G. William Rebeck
- Department of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia, United States of America
- * E-mail:
| |
Collapse
|
|
44
|
Gaillard F, Kuny S, Sauvé Y. Retinal distribution of Disabled-1 in a diurnal murine rodent, the Nile grass rat Arvicanthis niloticus. Exp Eye Res 2014; 125:236-43. [PMID: 24992207 DOI: 10.1016/j.exer.2014.06.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Revised: 06/18/2014] [Accepted: 06/19/2014] [Indexed: 11/29/2022]
Abstract
We sought to study the expression pattern of Disabled-1 (Dab1; an adaptor protein in the reelin pathway) in the cone-rich retina of a diurnal murine rodent. Expression was examined by western blotting and immunohistochemistry using well-established antibodies against Dab1 and various markers of retinal neurons. Western blots revealed the presence of Dab1 (80 kDa) in brain and retina of the Nile grass rat. Retinal immunoreactivity was predominant in soma and dendrites of horizontal cells as well as in amacrine cell bodies aligned at the INL/IPL border. Dab1(+) neurons in the inner retina do not stain for parvalbumin, calbindin, protein kinase C-alpha, choline acetyltransferase, glutamic acid decarboxylase, or tyrosine hydroxylase. They express, however, the glycine transporter GlyT1. They have small ovoid cell bodies (7.1 ± 1.06 μm in diameter) and bistratified terminal plexii in laminas a and b of the IPL. Dab1(+) amacrine cells are evenly distributed across the retina (2600 cells/mm(2)) in a fairly regular mosaic (regularity indexes ≈3.3-5.5). We conclude that retinal Dab1 in the adult Nile grass rat exhibits a dual cell patterning similar to that found in human. It is expressed in horizontal cells as well as in a subpopulation of glycinergic amacrine cells undetectable with antibodies against calcium-binding proteins. These amacrine cells are likely of the AII type.
Collapse
Affiliation(s)
- Frédéric Gaillard
- Department of Ophthalmology and Visual Science, University of Alberta, Edmonton, AB, Canada
| | - Sharee Kuny
- Department of Ophthalmology and Visual Science, University of Alberta, Edmonton, AB, Canada
| | - Yves Sauvé
- Department of Ophthalmology and Visual Science, University of Alberta, Edmonton, AB, Canada; Department of Physiology, University of Alberta, Edmonton, AB, Canada.
| |
Collapse
|
|
45
|
Divekar SD, Burrell TC, Lee JE, Weeber EJ, Rebeck GW. Ligand-induced homotypic and heterotypic clustering of apolipoprotein E receptor 2. J Biol Chem 2014; 289:15894-903. [PMID: 24755222 DOI: 10.1074/jbc.m113.537548] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
ApoE Receptor 2 (ApoER2) and the very low density lipoprotein receptor (VLDLR) are type I transmembrane proteins belonging to the LDLR family of receptors. They are neuronal proteins found in synaptic compartments that play an important role in neuronal migration during development. ApoER2 and VLDLR bind to extracellular glycoproteins, such as Reelin and F-spondin, which leads to phosphorylation of adaptor proteins and subsequent activation of downstream signaling pathways. It is thought that ApoER2 and VLDLR undergo clustering upon binding to their ligands, but no direct evidence of clustering has been shown. Here we show strong clustering of ApoER2 induced by the dimeric ligands Fc-RAP, F-spondin, and Reelin but relatively weak clustering with the ligand apoE in the absence of lipoproteins. This clustering involves numerous proteins besides ApoER2, including amyloid precursor protein and the synaptic adaptor protein PSD-95. Interestingly, we did not observe strong clustering of ApoER2 with VLDLR. Clustering was modulated by both extracellular and intracellular domains of ApoER2. Together, our data demonstrate that several multivalent ligands for ApoER2 induce clustering in transfected cells and primary neurons and that these complexes included other synaptic molecules, such as APP and PSD-95.
Collapse
Affiliation(s)
- Shailaja D Divekar
- From the Department of Neuroscience, Georgetown University Medical Center, Washington, D. C. 20007 and
| | - Teal C Burrell
- From the Department of Neuroscience, Georgetown University Medical Center, Washington, D. C. 20007 and
| | - Jennifer E Lee
- From the Department of Neuroscience, Georgetown University Medical Center, Washington, D. C. 20007 and
| | - Edwin J Weeber
- the Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa, Florida 33613
| | - G William Rebeck
- From the Department of Neuroscience, Georgetown University Medical Center, Washington, D. C. 20007 and
| |
Collapse
|
|
46
|
Moon HM, Wynshaw-Boris A. Cytoskeleton in action: lissencephaly, a neuronal migration disorder. WILEY INTERDISCIPLINARY REVIEWS-DEVELOPMENTAL BIOLOGY 2014; 2:229-45. [PMID: 23495356 DOI: 10.1002/wdev.67] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
During neocortical development, the extensive migratory movements of neurons from their place of birth to their final location are essential for the coordinated wiring of synaptic circuits and proper neurological function. Failure or delay in neuronal migration causes severe abnormalities in cortical layering, which consequently results in human lissencephaly ('smooth brain'), a neuronal migration disorder. The brains of lissencephaly patients have less-convoluted gyri in the cerebral cortex with impaired cortical lamination of neurons. Since microtubule (MT) and actin-associated proteins play important functions in regulating the dynamics of MT and actin cytoskeletons during neuronal migration, genetic mutations or deletions of crucial genes involved in cytoskeletal processes lead to lissencephaly in human and neuronal migration defects in mouse. During neuronal migration, MT organization and transport are controlled by platelet-activating factor acetylhydrolase isoform 1b regulatory subunit 1 (PAFAH1B1, formerly known as LIS1, Lissencephaly-1), doublecortin (DCX), YWHAE, and tubulin. Actin stress fibers are modulated by PAFAH1B1 (LIS1), DCX, RELN, and VLDLR (very low-density lipoprotein receptor)/LRP8 (low-density lipoprotein-related receptor 8, formerly known as APOER2). There are several important levels of crosstalk between these two cytoskeletal systems to establish accurate cortical patterning in development. The recent understanding of the protein networks that govern neuronal migration by regulating cytoskeletal dynamics, from human and mouse genetics as well as molecular and cellular analyses, provides new insights on neuronal migration disorders and may help us devise novel therapeutic strategies for such brain malformations.
Collapse
|
|
47
|
Eresheim C, Leeb C, Buchegger P, Nimpf J. Signaling by the extracellular matrix protein Reelin promotes granulosa cell proliferation in the chicken follicle. J Biol Chem 2014; 289:10182-91. [PMID: 24573679 DOI: 10.1074/jbc.m113.533489] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Chicken oocytes develop in follicles and reach an enormous size because of a massive uptake of yolk precursors such as very low density lipoprotein and vitellogenin. Oocyte growth is supported by theca cells and granulosa cells, which establish dynamic and highly organized cell layers surrounding the oocyte. The signaling processes orchestrating the development of these layered structures are largely unknown. Here we demonstrate that the Reelin pathway, which determines the development of layered neuronal structures in the brain, is also active in chicken follicles. Reelin, which is expressed in theca cells, triggers a signal in granulosa cells via apolipoprotein E receptor 2 and the very low density lipoprotein receptor, resulting in the phosphorylation of disabled-1 and consecutive activation of the phosphatidylinositol 3-kinase/Akt pathway. This signaling pathway supports the proliferation of differentiated granulosa cells to keep up with the demand of cells to cover the rapidly increasing surface of the giant germ cell.
Collapse
Affiliation(s)
- Christine Eresheim
- From the Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, 1030 Vienna, Austria
| | | | | | | |
Collapse
|
|
48
|
Abadesco AD, Cilluffo M, Yvone GM, Carpenter EM, Howell BW, Phelps PE. Novel Disabled-1-expressing neurons identified in adult brain and spinal cord. Eur J Neurosci 2014; 39:579-92. [PMID: 24251407 DOI: 10.1111/ejn.12416] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Revised: 09/19/2013] [Accepted: 10/08/2013] [Indexed: 12/12/2022]
Abstract
Components of the Reelin-signaling pathway are highly expressed in embryos and regulate neuronal positioning, whereas these molecules are expressed at low levels in adults and modulate synaptic plasticity. Reelin binds to Apolipoprotein E receptor 2 and Very-low-density lipoprotein receptors, triggers the phosphorylation of Disabled-1 (Dab1), and initiates downstream signaling. The expression of Dab1 marks neurons that potentially respond to Reelin, yet phosphorylated Dab1 is difficult to detect due to its rapid ubiquitination and degradation. Here we used adult mice with a lacZ gene inserted into the dab1 locus to first verify the coexpression of β-galactosidase (β-gal) in established Dab1-immunoreactive neurons and then identify novel Dab1-expressing neurons. Both cerebellar Purkinje cells and spinal sympathetic preganglionic neurons have coincident Dab1 protein and β-gal expression in dab1(lacZ/+) mice. Adult pyramidal neurons in cortical layers II-III and V are labeled with Dab1 and/or β-gal and are inverted in the dab1(lacZ/lacZ) neocortex, but not in the somatosensory barrel fields. Novel Dab1 expression was identified in GABAergic medial septum/diagonal band projection neurons, cerebellar Golgi interneurons, and small neurons in the deep cerebellar nuclei. Adult somatic motor neurons also express Dab1 and show ventromedial positioning errors in dab1-null mice. These findings suggest that: (i) Reelin regulates the somatosensory barrel cortex differently than other neocortical areas, (ii) most Dab1 medial septum/diagonal band neurons are probably GABAergic projection neurons, and (iii) positioning errors in adult mutant Dab1-labeled neurons vary from subtle to extensive.
Collapse
Affiliation(s)
- Autumn D Abadesco
- Department of Integrative Biology and Physiology, UCLA, Terasaki Life Science Building, 610 Charles Young Dr. E, Los Angeles, CA, 90095-7239, USA
| | | | | | | | | | | |
Collapse
|
|
49
|
Teixeira CM, Masachs N, Muhaisen A, Bosch C, Pérez-Martínez J, Howell B, Soriano E. Transient downregulation of Dab1 protein levels during development leads to behavioral and structural deficits: relevance for psychiatric disorders. Neuropsychopharmacology 2014; 39:556-68. [PMID: 24030361 PMCID: PMC3895234 DOI: 10.1038/npp.2013.226] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Revised: 08/09/2013] [Accepted: 08/11/2013] [Indexed: 02/07/2023]
Abstract
Psychiatric disorders have been hypothesized to originate during development, with genetic and environmental factors interacting in the etiology of disease. Therefore, developmentally regulated genes have received attention as risk modulators in psychiatric diseases. Reelin is an extracellular protein essential for neuronal migration and maturation during development, and its expression levels are reduced in psychiatric disorders. Interestingly, several perinatal insults that increase the risk of behavioral deficits alter Reelin signaling. However, it is not known whether a dysfunction in Reelin signaling during perinatal stages increases the risk of psychiatric disorders. Here we used a floxed dab1 allele to study whether a transient decrease in Dab1, a key component of the Reelin pathway, is sufficient to induce behavioral deficits related to psychiatric disorders. We found that transient Dab1 downregulation during perinatal stages leads to permanent abnormalities of structural layering in the neocortex and hippocampus. In contrast, conditional inactivation of the dab1 gene in the adult brain does not result in additional layering abnormalities. Furthermore, perinatal Dab1 downregulation causes behavior impairments in adult mice, such as deficits in memory, maternal care, pre-pulse inhibition, and response to cocaine. Some of these deficits were also found to be present in adolescence. We also show that D-cycloserine rescues the cognitive deficits observed in floxed dab1 mice with layering alterations in the hippocampus and neocortex. Our results indicate a causal relation between the downregulation of Dab1 protein levels during development and the structural and behavioral deficits associated with psychiatric diseases in the adult.
Collapse
Affiliation(s)
- Catia M Teixeira
- Department of Cell Biology, University of Barcelona, Barcelona, Spain,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain,Department of Cell Biology, University of Barcelona, Baldiri Reixac 10, Barcelona E-08028, Spain, Tel: +34 93 4037117, Fax: +34 93 4037116, E-mail: or
| | - Nuria Masachs
- Department of Cell Biology, University of Barcelona, Barcelona, Spain,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
| | - Ashraf Muhaisen
- Department of Cell Biology, University of Barcelona, Barcelona, Spain,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
| | - Carles Bosch
- Department of Cell Biology, University of Barcelona, Barcelona, Spain,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
| | | | - Brian Howell
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Eduardo Soriano
- Department of Cell Biology, University of Barcelona, Barcelona, Spain,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain,Fundación CIEN, Vallecas, Spain,Department of Cell Biology, University of Barcelona, Baldiri Reixac 10, Barcelona E-08028, Spain, Tel: +34 93 4037117, Fax: +34 93 4037116, E-mail: or
| |
Collapse
|
|
50
|
Lin VC, Huang CY, Lee YC, Yu CC, Chang TY, Lu TL, Huang SP, Bao BY. Genetic variations in TP53 binding sites are predictors of clinical outcomes in prostate cancer patients. Arch Toxicol 2014; 88:901-11. [PMID: 24448834 DOI: 10.1007/s00204-014-1196-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Accepted: 01/09/2014] [Indexed: 01/28/2023]
Abstract
Since the tumor protein p53 (TP53), a transcription factor, plays a crucial role in prostate cancer development and progression, we hypothesized that sequence variants in TP53 binding sites might affect clinical outcomes in patients with prostate cancer. We systematically evaluated 41 single nucleotide polymorphisms (SNPs) within genome-wide predicted TP53 binding sites in a cohort of 1,024 prostate cancer patients. The associations of these SNPs with prostate cancer characteristics and clinical outcomes after radical prostatectomy for localized disease and after androgen-deprivation therapy (ADT) for advanced disease were assessed by Kaplan-Meier analysis and Cox regression model. ARAP2 rs1444377 and TRPS1 rs722740 were associated with advanced stage prostate cancer. FRK rs171866 remained as a significant predictor for disease progression; DAB2 rs268091 and EXOC4 rs1149558 remained as significant predictors for prostate cancer-specific mortality (PCSM); and EXOC4 rs1149558 remained as a significant predictor for all-cause mortality after ADT in multivariate models that included clinicopathologic predictors. In addition, the numbers of protective genotypes at DAB2 rs268091 and EXOC4 rs1149558 showed a cumulative effect on PCSM (P for trend = 0.002). Our results suggested that SNPs within TP53 binding sites might be valuable biomarkers for prostate cancer outcome prediction.
Collapse
Affiliation(s)
- Victor C Lin
- Department of Urology, E-Da Hospital, Kaohsiung, Taiwan
| | | | | | | | | | | | | | | |
Collapse
|