• Cajal-Retzius cells
• Cerebral Cortex
• Hippocampus
• Migration
• Morphogenesis
• Mouse

• Animals
• Reelin Protein
• Cell Adhesion Molecules, Neuronal/metabolism
• Cell Adhesion Molecules, Neuronal/genetics
• Extracellular Matrix Proteins/metabolism
• Extracellular Matrix Proteins/genetics
• Cerebral Cortex/embryology
• Cerebral Cortex/cytology
• Cerebral Cortex/metabolism
• Nerve Tissue Proteins/metabolism
• Nerve Tissue Proteins/genetics
• Cell Movement
• Mice
• Serine Endopeptidases/metabolism
• Serine Endopeptidases/genetics
• Morphogenesis
• Neurons/metabolism
• Neurons/cytology
• Hippocampus/embryology
• Hippocampus/metabolism
• Mice, Knockout
• DNA-Binding Proteins/metabolism
• DNA-Binding Proteins/genetics
• CA1 Region, Hippocampal/embryology
• CA1 Region, Hippocampal/metabolism
• Neurogenesis

• ANR-17-EURE-0013 Agence Nationale de la Recherche
• FDT201904008366 Fondation pour la Recherche Medicale
• RM27J21IDXA7_CAJALIDENT Universite de Paris
• FDT201904008366 Fondation pour la Recherche Médicale
• RM27J21IDXA7_CAJALIDENT Idex Université Paris Cité

• TAp73
• glioblastoma
• glioblastoma stem cells
• natural compound
• stemness signature

• Tumor Protein p73/antagonists & inhibitors
• Tumor Protein p73/metabolism
• Tumor Protein p73/genetics
• Humans
• Glioblastoma/pathology
• Glioblastoma/metabolism
• Glioblastoma/genetics
• Glioblastoma/drug therapy
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Cell Line, Tumor
• Brain Neoplasms/pathology
• Brain Neoplasms/metabolism
• Brain Neoplasms/drug therapy
• Brain Neoplasms/genetics
• Gene Expression Regulation, Neoplastic/drug effects
• Animals

• LE021P17 Junta de Castilla y León
• LE022P20 Junta de Castilla y León
• PID2019-105169RB-I00 Ministerio de Ciencia e Innovación
• RTC-2015-3237-1 Ministerio de Ciencia e Innovación
• Junta de Castilla y León
• Ministerio de Ciencia e Innovación

• GABA
• development
• mouse
• somatosensory cortex
• synaptogenesis

• ERA-Net NEURON

• apoptosis
• atomic force microscopy
• flavonol
• metal-induced neurotoxicity
• pro-oxidative activity

• IP-2016-06-8415 Croatian Science Foundation

• Protein Isoforms/genetics
• Protein Isoforms/metabolism
• Tumor Suppressor Protein p53/metabolism
• Tumor Suppressor Protein p53/genetics
• Humans
• Alternative Splicing
• Animals
• Evolution, Molecular
• RNA, Messenger/metabolism
• RNA, Messenger/genetics
• Transcription Initiation Site
• Gene Expression Regulation

• FCE_3_2020_1_161877 Agencia Nacional de Investigación e Innovación
• Programa de Desarrollo de las Ciencias Básicas
• GACR 23-05951S Czech Science Foundation
• CZ.02.01.01/00/22_008/0 004 644 European Union and the State Budget of the Czech Republic
• Cancerforskningsfonden Norr, Cancerfonden, Vetenskapsradet
• MH CZ-DRO MMCI Ministry of Health

• DNp73
• TAp73
• brain development
• brain morphogenesis
• mouse brain organoids
• neurogenesis
• p53-family
• p73

• development of the nervous system
• sensorimotor processing

• Animals
• Cell Death
• Somatosensory Cortex/physiology
• Somatosensory Cortex/cytology
• Mice
• Pyramidal Cells/physiology
• Pyramidal Cells/metabolism
• Neocortex/cytology
• Neocortex/physiology
• GABAergic Neurons/physiology
• GABAergic Neurons/metabolism
• Male
• Vibrissae/physiology
• Female
• Mice, Inbred C57BL
• Neural Inhibition/physiology
• Neurons/physiology
• Neurons/metabolism

• 679175 EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013))
• 31003A_170037 Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)

• Cajal–Retzius cells
• adeno-associated virus
• adult hippocampus
• genetic modification
• neonatal intracerebroventricular injection
• ΔNp73-Cre

• Mice
• Animals
• Hippocampus/metabolism
• Neurons/physiology
• Neocortex
• Cell Movement

• PJT-169097 CIHR
• Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (NSERC)
• Canada Foundation for Innovation (CFI)
• Gouvernement du Canada | Canadian Institutes of Health Research (IRSC)
• Canada Research Chairs (Chaires de recherche du Canada)
• ALS Society of Canada (ALS Canada)

• Leptin
• TAp73
• TAp73γ
• cancer biology
• human
• mouse
• obesity
• oncogenesis
• p53

• Animals
• Dogs
• Humans
• Mice
• Carcinogenesis/genetics
• Cell Transformation, Neoplastic
• Exons
• Leptin/genetics
• Obesity
• Prostatic Neoplasms
• Tumor Protein p73/genetics
• Lymphoma

• P30 CA093373 NCI NIH HHS
• CA081237 NIH HHS
• CA224433 NIH HHS
• R01 CA081237 NCI NIH HHS
• CA093373 NIH HHS
• R01 CA224433 NCI NIH HHS
• National Institutes of Health
• Tobacco-Related Disease Research Program
• Center for Companion Animal Health, University of California, Davis

• Cajal-Retzius cells
• cerebral cortex
• choroid plexus
• fate specification
• multiciliogenesis
• neuronal differentiation
• neuronal identity

• Mice
• Animals
• Gene Regulatory Networks
• Cerebral Cortex/metabolism
• Neurons/metabolism
• Cell Differentiation/physiology
• Neurogenesis/genetics

• cell death in the nervous system
• epilepsy

• Humans
• Hippocampus/physiology
• Neurons/metabolism
• Pyramidal Cells/physiology
• Seizures/genetics
• Seizures/metabolism
• Memory Disorders/genetics
• Memory Disorders/metabolism

• Fondation Medic (MEDIC Foundation)
• Agence Nationale de la Recherche, ANR-15-CE16-0003-01 and ANR-19-CE16-0017-03 (AP) Fondation pour la recherche médicale, Équipe FRM DEQ20130326521 and EQU201903007836) (AP) Agence Nationale de la Recherche under “Investissements d’avenir” program, ANR-10-IAHU-01) (Imagine Institute)

• cell death
• cancer

• Animals
• Mice
• Cellular Senescence/genetics
• DNA-Binding Proteins/genetics
• Fatty Liver/genetics
• Fatty Liver/metabolism
• Fibroblasts
• Genes, Tumor Suppressor
• Inflammation/genetics
• Inflammation/metabolism
• Nuclear Proteins/genetics
• Protein Isoforms/genetics
• Tumor Protein p73/genetics
• Tumor Suppressor Proteins/genetics

• P30 CA093373 NCI NIH HHS
• R01 CA081237 NCI NIH HHS
• R01 CA224433 NCI NIH HHS
• U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)

Preservation of blood vessel integrity, which is critical for normal physiology and organ function, is controlled at multiple levels, including endothelial junctions. However, the mechanism that controls the adequate assembly of endothelial cell junctions is not fully defined. Here, we uncover TAp73 transcription factor as a vascular architect that orchestrates transcriptional programs involved in cell junction establishment and developmental blood vessel morphogenesis and identify Angiomotin (AMOT) as a TAp73 direct transcriptional target. Knockdown of p73 in endothelial cells not only results in decreased Angiomotin expression and localization at intercellular junctions, but also affects its downstream function regarding Yes-associated protein (YAP) cytoplasmic sequestration upon cell–cell contact. Analysis of adherens junctional morphology after p73-knockdown in human endothelial cells revealed striking alterations, particularly a sharp increase in serrated junctions and actin bundles appearing as stress fibers, both features associated with enhanced barrier permeability. In turn, stabilization of Angiomotin levels rescued those junctional defects, confirming that TAp73 controls endothelial junction dynamics, at least in part, through the regulation of Angiomotin. The observed defects in monolayer integrity were linked to hyperpermeability and reduced transendothelial electric resistance. Moreover, p73-knockout retinas showed a defective sprout morphology coupled with hemorrhages, highlighting the physiological relevance of p73 regulation in the maintenance of vessel integrity in vivo. We propose a new model in which TAp73 acts as a vascular architect integrating transcriptional programs that will impinge with Angiomotin/YAP signaling to maintain junctional dynamics and integrity, while balancing endothelial cell rearrangements in angiogenic vessels.

• Actin cytoskeleton
• Cell junctions
• Endothelial barrier integrity
• VE-cadherin and angiogenesis
• Vascular morphogenesis
• p53 family

The impact of Cajal-Retzius cells on the regulation of hippocampal circuits and related behaviors is unresolved. Here, we directly address this issue by impairing the glutamatergic output of Cajal-Retzius cells with the conditional ablation of vGluT2, which is their main vesicular glutamate transporter. Although two distinct conditional knockout lines do not reveal major alterations in hippocampal-layer organization and dendritic length of principal neurons or GABAergic cells, we find parallel deficits in specific hippocampal-dependent behaviors and in their putative underlying microcircuits. First, conditional knockout animals show increased innate anxiety and decreased feedforward GABAergic inhibition on dentate gyrus granule cells. Second, we observe impaired spatial memory processing, which is associated with decreased spine density and reduced AMPA/NMDA ratio of postsynaptic responses at the perforant- and entorhino-hippocampal pathways. We conclude that glutamate synaptically released by Cajal-Retzius cells is critical for the regulation of hippocampal microcircuits and specific types of behaviors.

Anstötz et al. report that postnatal hippocampal Cajal-Retzius cells use vGluT2 as their main glutamate vesicular transporter. Conditional inactivation of vGluT2 in mice reveals both behavioral and network alterations. The observed results indicate the involvement of Cajal-Retzius cells in the regulation of innate anxiety/spatial memory and in potentially related neuronal circuits.

• CP: Neuroscience
• anxiety
• development
• interneuron
• memory
• optogenetics
• spine
• transporter

Cortical wiring relies on guidepost cells and activity-dependent processes that are thought to act sequentially. Here, we show that the construction of layer 1 (L1), a main site of top-down integration, is regulated by crosstalk between transient Cajal-Retzius cells (CRc) and spontaneous activity of the thalamus, a main driver of bottom-up information. While activity was known to regulate CRc migration and elimination, we found that prenatal spontaneous thalamic activity and NMDA receptors selectively control CRc early density, without affecting their demise. CRc density, in turn, regulates the distribution of upper layer interneurons and excitatory synapses, thereby drastically impairing the apical dendrite activity of output pyramidal neurons. In contrast, postnatal sensory-evoked activity had a limited impact on L1 and selectively perturbed basal dendrites synaptogenesis. Collectively, our study highlights a remarkable interplay between thalamic activity and CRc in L1 functional wiring, with major implications for our understanding of cortical development.

•

Prenatal thalamic waves of activity regulate CRc density in L1

• CP: Neuroscience
• Cajal-Retzius cells
• E/I ratio
• NMDA receptors
• apical dendrites
• cortical development
• interneurons
• layer 1
• spines
• spontaneous activity
• thalamus

• embryonic telencephalon
• feline brain development
• genoarchitecture
• patterning
• prosomeric model

The Dmrt genes encode the transcription factor containing the DM (doublesex and mab-3) domain, an intertwined zinc finger-like DNA binding module. While Dmrt genes are mainly involved in the sexual development of various species, recent studies have revealed that Dmrt genes, which belong to the DmrtA subfamily, are differentially expressed in the embryonic brain and spinal cord and are essential for the development of the central nervous system. Herein, we summarize recent studies that reveal the multiple functions of the Dmrt genes in various aspects of vertebrate neural development, including brain patterning, neurogenesis, and the specification of neurons.

• DmrtA subfamily
• corticogenesis
• neurogenesis
• neuronal specification
• patterning

• Cortical hem
• Evolution
• Pallium
• Septum
• Ventral pallium

• actin cytoskeleton
• cell adhesion
• cell polarity
• central nervous system development
• neurogenic niche
• p53-family
• p73
• tissue architecture

• Cerebral cortex
• Fate acquisition
• Neuronal diversity
• Neuronal specification
• Ventral pallium

The Trp73 gene is involved in the regulation of multiple biological processes such as response to stress, differentiation and tissue architecture. This gene gives rise to structurally different N and C-terminal isoforms which lead to differences in its biological activity in a cell type dependent manner. However, there is a current lack of physiological models to study these isoforms. The aim of this study was to generate specific p73-isoform-deficient mouse embryonic stem cell lines using the CRISPR/Cas9 system. Their special features, self-renewal and pluripotency, make embryonic stem cells a useful research tool that allows the generation of cells from any of the three germ layers carrying specific inactivation of p73-isoforms. Characterization of the generated cell lines indicates that while the individual elimination of TA- or DN-p73 isoform is compatible with pluripotency, it results in alterations of the transcriptional profiles and the pluripotent state of the embryonic stem cells in an isoform-specific manner.

The p53 family has been widely studied for its role in various physiological and pathological processes. Imbalance of p53 family proteins may contribute to developmental abnormalities and pathologies in humans. This family exerts its functions through a profusion of isoforms that are generated by different promoter usage and alternative splicing in a cell type dependent manner. In particular, the Trp73 gene gives rise to TA and DN-p73 isoforms that confer p73 a dual nature. The biological relevance of p73 does not only rely on its tumor suppression effects, but on its pivotal role in several developmental processes. Therefore, the generation of cellular models that allow the study of the individual isoforms in a physiological context is of great biomedical relevance. We generated specific TA and DN-p73-deficient mouse embryonic stem cell lines using the CRISPR/Cas9 gene editing system and validated them as physiological bona fide p73-isoform knockout models. Global gene expression analysis revealed isoform-specific alterations of distinctive transcriptional networks. Elimination of TA or DN-p73 is compatible with pluripotency but prompts naïve pluripotent stem cell transition into the primed state, compromising adequate lineage differentiation, thus suggesting that differential expression of p73 isoforms acts as a rheostat during early cell fate determination.

• CRISPR/Cas9
• DNp73
• TAp73
• cell fate
• differentiation
• mouse embryonic stem cells (mESC), gene editing
• p73 isoforms
• pluripotency
• self-renewal

The p53 family of proteins comprises p53, p63, and p73, which share high structural and functional similarity. The two distinct promoters of each locus, the alternative splicing, and the alternative translation initiation sites enable the generation of numerous isoforms with different protein-interacting domains and distinct activities. The co-expressed p53/p73 isoforms have significant but distinct roles in carcinogenesis. Their activity is frequently impaired in human tumors including colorectal carcinoma due to dysregulated expression and a dominant-negative effect accomplished by some isoforms and p53 mutants. The interactions between isoforms are particularly important to understand the onset of tumor formation, progression, and therapeutic response. The understanding of the p53/p73 network can contribute to the development of new targeted therapies.

The p53 tumor suppressor protein is crucial for cell growth control and the maintenance of genomic stability. Later discovered, p63 and p73 share structural and functional similarity with p53. To understand the p53 pathways more profoundly, all family members should be considered. Each family member possesses two promoters and alternative translation initiation sites, and they undergo alternative splicing, generating multiple isoforms. The resulting isoforms have important roles in carcinogenesis, while their expression is dysregulated in several human tumors including colorectal carcinoma, which makes them potential targets in cancer treatment. Their activities arise, at least in part, from the ability to form tetramers that bind to specific DNA sequences and activate the transcription of target genes. In this review, we summarize the current understanding of the biological activities and regulation of the p53/p73 isoforms, highlighting their role in colorectal tumorigenesis. The analysis of the expression patterns of the p53/p73 isoforms in human cancers provides an important step in the improvement of cancer therapy. Furthermore, the interactions among the p53 family members which could modulate normal functions of the canonical p53 in tumor tissue are described. Lastly, we emphasize the importance of clinical studies to assess the significance of combining the deregulation of different members of the p53 family to define the outcome of the disease.

• colorectal cancer
• isoform crosstalk
• p53 family
• p53 isoforms
• p73 isoforms

Small proline-rich protein 2A and 2D (SPRR2A and SPRR2D) are structure proteins of cornified cell envelopes and function as a protective barrier against diverse external insults. However, the role of SPRR2A/2D in chronic inflammation remains unclear. Here, we showed that SPRR2A/2D expression is controlled by a regulatory loop formed by RNA-binding protein RBM38 and tumor suppressor p73. We also found that RBM38-mediated expression of SPRR2A/2D was p73-dependent and that induction of SPRR2A/2D during keratinocyte differentiation was dependent on both p73 and Rbm38. Furthermore, We found that Rbm38^−/−;Trp73^+/− mice exhibited weak expression of SPRR2A/2D in multiple tissues and were susceptible to systemic chronic inflammation. Together, our data reveal that SPRR2A/2D are novel targets of the RBM38-p73 loop and contribute to p73-dependent suppression of chronic inflammation.

Small proline-rich protein 2A and 2D (SPRR2A and SPRR2D) provide barrier function in terminally differentiated stratified squamous epithelia through the epidermal differentiation complex. However, little is known how SPRR2A/2D expression is controlled and their role in chronic inflammation. Here, we showed that that SPRR2A/2D expression is controlled by a regulatory loop formed by RNA-binding protein RBM38 and tumor suppressor p73. Specifically, we found that SPRR2A/2D expression was induced by ectopic expression of RBM38 or p73 but suppressed by knockout of Rbm38 or p73. We also found that RBM38-mediated expression of SPRR2A/2D was p73-dependent and that induction of SPRR2A/2D during keratinocyte differentiation was dependent on both p73 and Rbm38. Additionally, we found that SPRR2A/2D expression was closely associated with p73 expression in normal and cancerous tissues. To determine the biological function of the RBM38-p73 loop potentially via SPRR2A/2D, we generated a cohort of wild-type, Rbm38^−/−, Trp73^+/−, and Rbm38^−/−;Trp73^+/− mice. We found that Rbm38^−/−;Trp73^+/− mice had a much shorter lifespan than that for Rbm38^−/−—and to a lesser extent for Trp73^+/− mice—but were less prone to spontaneous tumors than Trp73^+/− or Rbm38^−/− mice. We also found that Rbm38^−/−;Trp73^+/− mice exhibited weak expression of SPRR2A/2D in multiple tissues and were susceptible to systemic chronic inflammation, suggesting that decreased SPRR2A/2D expression is likely responsible for chronic inflammation in Rbm38^−/−;Trp73^+/− mice, leading to a shortened lifespan. Together, our data reveal that SPRR2A/2D are novel targets of the RBM38-p73 loop and contribute to p73-dependent suppression of chronic inflammation.

• P73
• SPRR2A/SPRR2D
• inflammation
• tumor suppression

• P30 CA093373 NCI NIH HHS
• R01 CA081237 NCI NIH HHS
• R01 CA250338 NCI NIH HHS
• CA081237; CA250338 ; CA093373 NCI NIH HHS

• Cajal-Retzius neurons
• Cortex
• Development
• Hippocampus
• Molecular profiling
• Single-cell transcriptomics

• Commissural septum
• Diagonal band
• Extended amygdala
• Lateral hypothalamus
• Preoptic area
• Prethalamic eminence
• Quail-chick chimeras
• Tbr1

• distalless
• genoarchitectural analysis
• liminar alar domain
• mouse
• pregeniculate nucleus
• preincertal nucleus
• prethalamus
• reticular nucleus
• subgeniculate nucleus
• zona incerta
• zona limitans rostral shell

• Animals
• Animals, Newborn
• Chromosome Mapping/methods
• Female
• Gene Expression
• Homeodomain Proteins/biosynthesis
• Homeodomain Proteins/genetics
• Lac Operon/genetics
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Pregnancy
• Thalamus/embryology
• Thalamus/growth & development
• Thalamus/metabolism
• Zebrafish

• R01 MH049428 NIMH NIH HHS
• R37 MH049428 NIMH NIH HHS
• National Institute of Mental Health
• Séneca Foundation (Fundación Séneca), Spain

• ANGPT1
• ETS2
• GBM
• Rebastinib
• Tie2
• deltaNp73

• FDX1
• FDX2
• iron metabolism
• iron response element
• mRNA stability

• GABA
• development
• interneuron
• network
• p73
• reelin

• cancer
• circRNAs
• lncRNAs
• miRNAs
• p53
• p63
• p73

Programmed cell death and early activity contribute to the emergence of functional cortical circuits. While most neuronal populations are scaled-down by death, some subpopulations are entirely eliminated, raising the question of the importance of such demise for cortical wiring. Here, we addressed this issue by focusing on Cajal-Retzius neurons (CRs), key players in cortical development that are eliminated in postnatal mice in part via Bax-dependent apoptosis. Using Bax-conditional mutants and CR hyperpolarization, we show that the survival of electrically active subsets of CRs triggers an increase in both dendrite complexity and spine density of upper layer pyramidal neurons, leading to an excitation/inhibition imbalance. The survival of these CRs is induced by hyperpolarization, highlighting an interplay between early activity and neuronal elimination. Taken together, our study reveals a novel activity-dependent programmed cell death process required for the removal of transient immature neurons and the proper wiring of functional cortical circuits.

• Cajal-Retzius neurons
• apoptosis
• cortical development
• developmental biology
• excitation/inhibition ratio
• mouse
• neuronal activity
• neuroscience
• transient

• TP73
• Trp73
• p73

• apoptosis
• critical period
• development
• neocortex
• neuronal activity
• programmed cell death

• BDNF
• environmental enrichment
• interneuron
• neurogenesis
• plasticity

p73 transcription factor belongs to one of the most important gene families in vertebrate biology, the p53-family. Trp73 gene, like the other family members, generates multiple isoforms named TA and DNp73, with different and, sometimes, antagonist functions. Although p73 shares many biological functions with p53, it also plays distinct roles during development. Trp73 null mice (p73KO from now on) show multiple phenotypes as gastrointestinal and cranial hemorrhages, rhinitis and severe central nervous system defects. Several groups, including ours, have revisited the apparently unrelated phenotypes observed in total p73KO and revealed a novel p73 function in the organization of ciliated epithelia in brain and trachea, but also an essential role as regulator of ependymal planar cell polarity. Unlike p73KO or TAp73KO mice, tumor-prone Trp53−/− mice (p53KO) do not present ependymal ciliary or planar cell polarity defects, indicating that regulation of ciliogenesis and PCP is a p73-specific function. Thus, loss of ciliary biogenesis and epithelial organization might be a common underlying cause of the diverse p73KO-phenotypes, highlighting Trp73 role as an architect of the epithelial tissue. In this review we would like to discuss the data regarding p73 role as regulator of ependymal cell ciliogenesis and PCP, supporting the view of the Trp73-mutant mice as a model that uncouples ciliogenesis from PCP and a possible model of human congenital hydrocephalus.

• DNp73
• TAp73
• actin cytoskeleton
• ciliogenesis
• ependymal cells
• hydrocephalus
• microtubules
• planar cell polarity