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Goyal S, Tibrewal S, Ratna R, Vanita V. Genetic and environmental factors contributing to anophthalmia and microphthalmia: Current understanding and future directions. World J Clin Pediatr 2025; 14:101982. [PMID: 40491727 PMCID: PMC11947877 DOI: 10.5409/wjcp.v14.i2.101982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 02/19/2025] [Accepted: 02/25/2025] [Indexed: 03/18/2025] Open
Abstract
Anophthalmia is defined as a complete absence of one eye or both the eyes, while microphthalmia represents the presence of a small eye within the orbit. The estimated birth prevalence for anophthalmia is approximately 3 per 100000 live births, and for microphthalmia, it is around 14 per 100000 live births. However, combined evidence suggests that the prevalence of these malformations could be as high as 30 per 100000 individuals. Microphthalmia is reported to occur in 3.2% to 11.2% of blind children. Anophthalmia and microphthalmia (A/M) are part of a phenotypic spectrum alongside ocular coloboma, hypothesized to share a common genetic basis. Both A/M can occur in isolation or as part of a syndrome. Their complex etiology involves chromosomal aberrations, monogenic inheritance pattern, and the contribution of environmental factors such as gestational-acquired infections, maternal vitamin A deficiency (VAD), exposure to X-rays, solvent misuse, and thalidomide exposure. A/M exhibit significant clinical and genetic heterogeneity with over 90 genes identified so far. Familial cases of A/M have a complex genetic basis, including all Mendelian modes of inheritance, i.e., autosomal dominant, recessive, and X-linked. Most cases arise sporadically due to de novo mutations. Examining gene expression during eye development and the effects of various environmental variables will help us better understand the phenotypic heterogeneity found in A/M, leading to more effective diagnosis and management strategies. The present review focuses on key genetic factors, developmental abnormalities, and environmental modifiers linked with A/M. It also emphasizes at potential research areas including multiomic methods and disease modeling with induced pluripotent stem cell technologies, which aim to create innovative treatment options.
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Affiliation(s)
- Shiwali Goyal
- Department of Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Rockville, MD 20852, United States
| | - Shailja Tibrewal
- Department of Pediatric Ophthalmology, Dr. Shroff’s Charity Eye Hospital, New Delhi 110002, Delhi, India
- Department of Ocular Genetics (Center for Unknown and Rare Eye Diseases), Dr. Shroff’s Charity Eye Hospital, New Delhi 110002, Delhi, India
| | - Ria Ratna
- Department of Ocular Genetics (Center for Unknown and Rare Eye Diseases), Dr. Shroff’s Charity Eye Hospital, New Delhi 110002, Delhi, India
| | - Vanita Vanita
- Department of Human Genetics, Guru Nanak Dev University, Amritsar 143005, Punjab, India
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Owusu-Ansah K, Thomas KN, Cox K, Pham DL, Chen WL, Ko ML, Golding MC, Ko GYP. Preconception Paternal Alcohol Consumption Elicits Postnatal Changes in Neural Retinas of the Offspring. Invest Ophthalmol Vis Sci 2025; 66:16. [PMID: 39913164 PMCID: PMC11806431 DOI: 10.1167/iovs.66.2.16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 01/10/2025] [Indexed: 02/07/2025] Open
Abstract
Purpose This study aims to determine the impact of preconception paternal alcohol consumption (PPAC) on retinal function and morphology in PPAC-offspring. Fetal alcohol spectrum disorder (FASD)-related ocular defects caused by maternal alcohol exposure has been well investigated, but the influence of PPAC on offspring eyes remains unknown. Methods Adult C57BL/6J male mice were exposed to either 10% ethanol or water (control) for six weeks and bred to naïve females. Dark-adapted retinal light responses at two, four, and six months old were assessed using electroretinography (ERG) for the offspring born to PPAC and control males. The thicknesses of whole retinas and different retinal layers of the control and PPAC-offspring were analyzed at two and six months old. Results Some PPAC-offspring had only one developed eye. ERG a- and b-wave amplitudes were reduced in PPAC-offspring compared to controls, with a more pronounced effect in females. PPAC had significant effects on inner retinal function. At two months old, there was a significant thinning of the retinal inner nuclear and inner plexiform layers in PPAC-offspring. At six months old, the retinal thickness and ERG amplitudes were similar between both treatment groups. Conclusions This study provides pioneering evidence that PPAC contributes to FASD-related ocular defects including negative impacts on retinal light responses and retinal thinning in young adult offspring. Thus the adverse impact of paternal alcohol consumption prior to conception on their offspring (from childhood to early adulthood) should be considered as seriously as the maternal contribution to FASD.
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Affiliation(s)
- Kofi Owusu-Ansah
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States
- Texas A&M Institute for Neuroscience, Texas A&M University, College Station, Texas, United States
| | - Kara N. Thomas
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States
| | - Kelsey Cox
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States
| | - Dylan L. Pham
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States
- Department of Medical Physiology, School of Medicine, Texas A&M University, Bryan, Texas, United States
| | - Wei-Lin Chen
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States
- Department of Physics, National Chung Hsing University, Taichung City, Taiwan
| | - Michael Lee Ko
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States
- Department of Biology, Division of Natural and Physical Sciences, Blinn College, Bryan, Texas, United States
| | - Michael C. Golding
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States
| | - Gladys Yi-Ping Ko
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States
- Texas A&M Institute for Neuroscience, Texas A&M University, College Station, Texas, United States
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De Magalhães CG, Cvekl A, Jaeger RG, Yan CYI. Lens placode modulates extracellular matrix formation during early eye development. Differentiation 2024; 138:100792. [PMID: 38935992 PMCID: PMC11247415 DOI: 10.1016/j.diff.2024.100792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 06/13/2024] [Accepted: 06/20/2024] [Indexed: 06/29/2024]
Abstract
The role extracellular matrix (ECM) in multiple events of morphogenesis has been well described, little is known about its specific role in early eye development. One of the first morphogenic events in lens development is placodal thickening, which converts the presumptive lens ectoderm from cuboidal to pseudostratified epithelium. This process occurs in the anterior pre-placodal ectoderm when the optic vesicle approaches the cephalic ectoderm and is regulated by transcription factor Pax6 and secreted BMP4. Since cells and ECM have a dynamic relationship of interdependence and modulation, we hypothesized that the ECM evolves with cell shape changes during lens placode formation. This study investigates changes in optic ECM including both protein distribution deposition, extracellular gelatinase activity and gene expression patterns during early optic development using chicken and mouse models. In particular, the expression of Timp2, a metalloprotease inhibitor, corresponds with a decrease in gelatinase activity within the optic ECM. Furthermore, we demonstrate that optic ECM remodeling depends on BMP signaling in the placode. Together, our findings suggest that the lens placode plays an active role in remodeling the optic ECM during early eye development.
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Affiliation(s)
- Cecília G De Magalhães
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, 05508-900, Brazil
| | - Ales Cvekl
- Department of Ophthalmology and Visual Sciences and Genetics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Ruy G Jaeger
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, 05508-900, Brazil
| | - C Y Irene Yan
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, 05508-900, Brazil.
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De Magalhães CG, Cvekl A, Jaeger RG, Yan CYI. Lens Placode Modulates Extracellular Matrix Formation During Early Eye Development. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.11.30.569417. [PMID: 38076974 PMCID: PMC10705410 DOI: 10.1101/2023.11.30.569417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/07/2024]
Abstract
The role extracellular matrix (ECM) in multiple events of morphogenesis has been well described, little is known about its specific role in early eye development. One of the first morphogenic events in lens development is placodal thickening, which converts the presumptive lens ectoderm from cuboidal to pseudostratified epithelium. This process occurs in the anterior pre-placodal ectoderm when the optic vesicle approaches the cephalic ectoderm. Since cells and ECM have a dynamic relationship of interdependence and modulation, we hypothesized that the ECM evolves with cell shape changes during lens placode formation. This study investigates changes in optic ECM including both protein distribution deposition, extracellular gelatinase activity and gene expression patterns during early optic development using chicken and mouse models. In particular, the expression of Timp2 , a metalloprotease inhibitor, corresponds with a decrease in gelatinase activity within the optic ECM. Furthermore, we demonstrate that optic ECM remodeling depends on BMP signaling in the placode. Together, our findings suggest that the lens placode plays an active role in remodeling the optic ECM during early eye development.
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Li M, Sun H, Hou Z, Hao S, Jin L, Wang B. Engineering the Physical Microenvironment into Neural Organoids for Neurogenesis and Neurodevelopment. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2306451. [PMID: 37771182 DOI: 10.1002/smll.202306451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 09/04/2023] [Indexed: 09/30/2023]
Abstract
Understanding the signals from the physical microenvironment is critical for deciphering the processes of neurogenesis and neurodevelopment. The discovery of how surrounding physical signals shape human developing neurons is hindered by the bottleneck of conventional cell culture and animal models. Notwithstanding neural organoids provide a promising platform for recapitulating human neurogenesis and neurodevelopment, building neuronal physical microenvironment that accurately mimics the native neurophysical features is largely ignored in current organoid technologies. Here, it is discussed how the physical microenvironment modulates critical events during the periods of neurogenesis and neurodevelopment, such as neural stem cell fates, neural tube closure, neuronal migration, axonal guidance, optic cup formation, and cortical folding. Although animal models are widely used to investigate the impacts of physical factors on neurodevelopment and neuropathy, the important roles of human stem cell-derived neural organoids in this field are particularly highlighted. Considering the great promise of human organoids, building neural organoid microenvironments with mechanical forces, electrophysiological microsystems, and light manipulation will help to fully understand the physical cues in neurodevelopmental processes. Neural organoids combined with cutting-edge techniques, such as advanced atomic force microscopes, microrobots, and structural color biomaterials might promote the development of neural organoid-based research and neuroscience.
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Affiliation(s)
- Minghui Li
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Heng Sun
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China
| | - Zongkun Hou
- Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, Engineering Research Center of Cellular Immunotherapy of Guizhou Province, School of Biology and Engineering/School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550025, China
| | - Shilei Hao
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China
| | - Liang Jin
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China
| | - Bochu Wang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400045, China
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Bellapianta A, Cetkovic A, Bolz M, Salti A. Retinal Organoids and Retinal Prostheses: An Overview. Int J Mol Sci 2022; 23:2922. [PMID: 35328339 PMCID: PMC8953078 DOI: 10.3390/ijms23062922] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/04/2022] [Accepted: 03/06/2022] [Indexed: 01/27/2023] Open
Abstract
Despite the progress of modern medicine in the last decades, millions of people diagnosed with retinal dystrophies (RDs), such as retinitis pigmentosa, or age-related diseases, such as age-related macular degeneration, are suffering from severe visual impairment or even legal blindness. On the one hand, the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) and the progress of three-dimensional (3D) retinal organoids (ROs) technology provide a great opportunity to study, understand, and even treat retinal diseases. On the other hand, research advances in the field of electronic retinal prosthesis using inorganic photovoltaic polymers and the emergence of organic semiconductors represent an encouraging therapeutical strategy to restore vision to patients at the late onset of the disease. This review will provide an overview of the latest advancement in both fields. We first describe the retina and the photoreceptors, briefly mention the most used RD animal models, then focus on the latest RO differentiation protocols, carry out an overview of the current technology on inorganic and organic retinal prostheses to restore vision, and finally summarize the potential utility and applications of ROs.
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Affiliation(s)
| | | | | | - Ahmad Salti
- Center for Medical Research, Faculty of Medicine, University Clinic for Ophthalmology and Optometry, Johannes Kepler University Linz, 4020 Linz, Austria; (A.B.); (A.C.); (M.B.)
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Devos L, Agnès F, Edouard J, Simon V, Legendre L, El Khallouki N, Barbachou S, Sohm F, Rétaux S. Eye morphogenesis in the blind Mexican cavefish. Biol Open 2021; 10:bio059031. [PMID: 34590124 PMCID: PMC8565469 DOI: 10.1242/bio.059031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 09/24/2021] [Indexed: 01/13/2023] Open
Abstract
The morphogenesis of the vertebrate eye consists of a complex choreography of cell movements, tightly coupled to axial regionalization and cell type specification processes. Disturbances in these events can lead to developmental defects and blindness. Here, we have deciphered the sequence of defective events leading to coloboma in the embryonic eye of the blind cavefish of the species Astyanax mexicanus. Using comparative live imaging on targeted enhancer-trap Zic1:hsp70:GFP reporter lines of both the normal, river-dwelling morph and the cave morph of the species, we identified defects in migratory cell behaviours during evagination that participate in the reduced optic vesicle size in cavefish, without proliferation defect. Further, impaired optic cup invagination shifts the relative position of the lens and contributes to coloboma in cavefish. Based on these results, we propose a developmental scenario to explain the cavefish phenotype and discuss developmental constraints to morphological evolution. The cavefish eye appears as an outstanding natural mutant model to study molecular and cellular processes involved in optic region morphogenesis.
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Affiliation(s)
- Lucie Devos
- Paris-Saclay Institute of Neuroscience, CNRS, Université Paris-Saclay, 91198 Gif sur Yvette, France
| | - François Agnès
- Paris-Saclay Institute of Neuroscience, CNRS, Université Paris-Saclay, 91198 Gif sur Yvette, France
| | - Joanne Edouard
- AMAGEN, CNRS, INRA, Université Paris-Saclay, 91198, Gif sur Yvette, France
| | - Victor Simon
- Paris-Saclay Institute of Neuroscience, CNRS, Université Paris-Saclay, 91198 Gif sur Yvette, France
- AMAGEN, CNRS, INRA, Université Paris-Saclay, 91198, Gif sur Yvette, France
| | - Laurent Legendre
- AMAGEN, CNRS, INRA, Université Paris-Saclay, 91198, Gif sur Yvette, France
| | - Naima El Khallouki
- AMAGEN, CNRS, INRA, Université Paris-Saclay, 91198, Gif sur Yvette, France
| | - Sosthène Barbachou
- AMAGEN, CNRS, INRA, Université Paris-Saclay, 91198, Gif sur Yvette, France
| | - Frédéric Sohm
- AMAGEN, CNRS, INRA, Université Paris-Saclay, 91198, Gif sur Yvette, France
| | - Sylvie Rétaux
- Paris-Saclay Institute of Neuroscience, CNRS, Université Paris-Saclay, 91198 Gif sur Yvette, France
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Lee JH, Park HS, Holmes DP. Elastic Instabilities Govern the Morphogenesis of the Optic Cup. PHYSICAL REVIEW LETTERS 2021; 127:138102. [PMID: 34623834 DOI: 10.1103/physrevlett.127.138102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 08/06/2021] [Indexed: 06/13/2023]
Abstract
Because the normal operation of the eye depends on sensitive morphogenetic processes for its eventual shape, developmental flaws can lead to wide-ranging ocular defects. However, the physical processes and mechanisms governing ocular morphogenesis are not well understood. Here, using analytical theory and nonlinear shell finite-element simulations, we show, for optic vesicles experiencing matrix-constrained growth, that elastic instabilities govern the optic cup morphogenesis. By capturing the stress amplification owing to mass increase during growth, we show that the morphogenesis is driven by two elastic instabilities analogous to the snap through in spherical shells, where the second instability is sensitive to the optic cup geometry. In particular, if the optic vesicle is too slender, it will buckle and break axisymmetry, thus, preventing normal development. Our results shed light on the morphogenetic mechanisms governing the formation of a functional biological system and the role of elastic instabilities in the shape selection of soft biological structures.
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Affiliation(s)
- Jeong-Ho Lee
- Department of Mechanical Engineering, Boston University, Boston, Massachusetts 02215, USA
| | - Harold S Park
- Department of Mechanical Engineering, Boston University, Boston, Massachusetts 02215, USA
| | - Douglas P Holmes
- Department of Mechanical Engineering, Boston University, Boston, Massachusetts 02215, USA
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Casey MA, Lusk S, Kwan KM. Build me up optic cup: Intrinsic and extrinsic mechanisms of vertebrate eye morphogenesis. Dev Biol 2021; 476:128-136. [PMID: 33811855 PMCID: PMC8848517 DOI: 10.1016/j.ydbio.2021.03.023] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/25/2021] [Accepted: 03/26/2021] [Indexed: 12/16/2022]
Abstract
The basic structure of the eye, which is crucial for visual function, is established during the embryonic process of optic cup morphogenesis. Molecular pathways of specification and patterning are integrated with spatially distinct cell and tissue shape changes to generate the eye, with discrete domains and structural features: retina and retinal pigment epithelium enwrap the lens, and the optic fissure occupies the ventral surface of the eye and optic stalk. Interest in the underlying cell biology of eye morphogenesis has led to a growing body of work, combining molecular genetics and imaging to quantify cellular processes such as adhesion and actomyosin activity. These studies reveal that intrinsic machinery and spatiotemporally specific extrinsic inputs collaborate to control dynamics of cell movements and morphologies. Here we consider recent advances in our understanding of eye morphogenesis, with a focus on the mechanics of eye formation throughout vertebrate systems, including insights and potential opportunities using organoids, which may provide a tractable system to test hypotheses from embryonic models.
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Affiliation(s)
- Macaulie A Casey
- Department of Human Genetics, University of Utah, Salt Lake City, UT, 84112, USA
| | - Sarah Lusk
- Department of Human Genetics, University of Utah, Salt Lake City, UT, 84112, USA
| | - Kristen M Kwan
- Department of Human Genetics, University of Utah, Salt Lake City, UT, 84112, USA.
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Harding P, Cunha DL, Moosajee M. Animal and cellular models of microphthalmia. THERAPEUTIC ADVANCES IN RARE DISEASE 2021; 2:2633004021997447. [PMID: 37181112 PMCID: PMC10032472 DOI: 10.1177/2633004021997447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 02/02/2021] [Indexed: 05/16/2023]
Abstract
Microphthalmia is a rare developmental eye disorder affecting 1 in 7000 births. It is defined as a small (axial length ⩾2 standard deviations below the age-adjusted mean) underdeveloped eye, caused by disruption of ocular development through genetic or environmental factors in the first trimester of pregnancy. Clinical phenotypic heterogeneity exists amongst patients with varying levels of severity, and associated ocular and systemic features. Up to 11% of blind children are reported to have microphthalmia, yet currently no treatments are available. By identifying the aetiology of microphthalmia and understanding how the mechanisms of eye development are disrupted, we can gain a better understanding of the pathogenesis. Animal models, mainly mouse, zebrafish and Xenopus, have provided extensive information on the genetic regulation of oculogenesis, and how perturbation of these pathways leads to microphthalmia. However, differences exist between species, hence cellular models, such as patient-derived induced pluripotent stem cell (iPSC) optic vesicles, are now being used to provide greater insights into the human disease process. Progress in 3D cellular modelling techniques has enhanced the ability of researchers to study interactions of different cell types during eye development. Through improved molecular knowledge of microphthalmia, preventative or postnatal therapies may be developed, together with establishing genotype-phenotype correlations in order to provide patients with the appropriate prognosis, multidisciplinary care and informed genetic counselling. This review summarises some key discoveries from animal and cellular models of microphthalmia and discusses how innovative new models can be used to further our understanding in the future. Plain language summary Animal and Cellular Models of the Eye Disorder, Microphthalmia (Small Eye) Microphthalmia, meaning a small, underdeveloped eye, is a rare disorder that children are born with. Genetic changes or variations in the environment during the first 3 months of pregnancy can disrupt early development of the eye, resulting in microphthalmia. Up to 11% of blind children have microphthalmia, yet currently no treatments are available. By understanding the genes necessary for eye development, we can determine how disruption by genetic changes or environmental factors can cause this condition. This helps us understand why microphthalmia occurs, and ensure patients are provided with the appropriate clinical care and genetic counselling advice. Additionally, by understanding the causes of microphthalmia, researchers can develop treatments to prevent or reduce the severity of this condition. Animal models, particularly mice, zebrafish and frogs, which can also develop small eyes due to the same genetic/environmental changes, have helped us understand the genes which are important for eye development and can cause birth eye defects when disrupted. Studying a patient's own cells grown in the laboratory can further help researchers understand how changes in genes affect their function. Both animal and cellular models can be used to develop and test new drugs, which could provide treatment options for patients living with microphthalmia. This review summarises the key discoveries from animal and cellular models of microphthalmia and discusses how innovative new models can be used to further our understanding in the future.
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Affiliation(s)
| | | | - Mariya Moosajee
- UCL Institute of Ophthalmology, 11-43 Bath
Street, London, EC1V 9EL, UK
- Moorfields Eye Hospital NHS Foundation Trust,
London, UK
- Great Ormond Street Hospital for Children NHS
Foundation Trust, London, UK
- The Francis Crick Institute, London, UK
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O'Hara-Wright M, Gonzalez-Cordero A. Retinal organoids: a window into human retinal development. Development 2020; 147:147/24/dev189746. [PMID: 33361444 PMCID: PMC7774906 DOI: 10.1242/dev.189746] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Retinal development and maturation are orchestrated by a series of interacting signalling networks that drive the morphogenetic transformation of the anterior developing brain. Studies in model organisms continue to elucidate these complex series of events. However, the human retina shows many differences from that of other organisms and the investigation of human eye development now benefits from stem cell-derived organoids. Retinal differentiation methods have progressed from simple 2D adherent cultures to self-organising micro-physiological systems. As models of development, these have collectively offered new insights into the previously unexplored early development of the human retina and informed our knowledge of the key cell fate decisions that govern the specification of light-sensitive photoreceptors. Although the developmental trajectories of other retinal cell types remain more elusive, the collation of omics datasets, combined with advanced culture methodology, will enable modelling of the intricate process of human retinogenesis and retinal disease in vitro. Summary: Retinal organoid systems derived from human pluripotent stem cells are micro-physiological systems that offer new insights into previously unexplored human retina development.
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Affiliation(s)
- Michelle O'Hara-Wright
- Stem Cell Medicine Group, Children's Medical Research Institute, University of Sydney, Westmead, 2145, NSW, Australia.,School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Westmead, 2145, NSW, Australia
| | - Anai Gonzalez-Cordero
- Stem Cell Medicine Group, Children's Medical Research Institute, University of Sydney, Westmead, 2145, NSW, Australia .,School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Westmead, 2145, NSW, Australia
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Li J, Zhang JS, Zhao JY, Han GG. Role of Smad4 from ocular surface ectoderm in retinal vasculature development. Int J Ophthalmol 2020; 13:231-238. [PMID: 32090031 DOI: 10.18240/ijo.2020.02.05] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Accepted: 12/09/2019] [Indexed: 11/23/2022] Open
Abstract
AIM To investigate how signals from lens regulate retinal vascular development and neovascularization. METHODS Le-Cre transgenic mouse line was employed to inactivate Smad4 in the surface ectoderm selectively. Standard histological and whole-mount retina staining were employed to reveal morphological changes of retinal vasculature in Smad4 defective eye. cDNA microarray and subsequent analyses were conducted to investigate the molecular mechanism underlying the vascular phenotype. Quantitative polymerase chain reaction (qPCR) was carried out to verify the microarrays results. RESULTS We found that inactivation of Smad4 specifically on surface ectoderm leads to a variety of retinal vasculature anomalies. Microarray analyses and qPCR revealed that Sema3c, Sema3e, Nrp1, Tie1, Sox7, Sox17, and Sox18 are significantly affected in the knockout retinas at different developmental stages, suggesting that ocular surface ectoderm-derived Smad4 can signal to the retina and regulates various angiogenic signaling in the retina. CONCLUSION Our data suggest that the cross-talk between ocular surface ectoderm and retina is important for retinal vasculature development, and Smad4 regulates various signaling associated with sprouting angiogenesis, vascular remodeling and maturation in the retina of mice.
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Affiliation(s)
- Jing Li
- Tianjin Eye Hospital, Tianjin Eye Institute, Tianjin Key Lab of Ophthalmology and Visual Science, Nankai University, Tianjin 300000, China
| | - Jin-Song Zhang
- Shenyang Aier Excellence Eye Hospital, Shenyang 110000, Liaoning Province, China
| | - Jiang-Yue Zhao
- Department of Ophthalmology, the Fourth Affiliated Hospital of China Medical University, Eye Hospital of China Medical University, Key Lens Research Laboratory, Shenyang 110000, Liaoning Province, China
| | - Guo-Ge Han
- Tianjin Eye Hospital, Tianjin Eye Institute, Tianjin Key Lab of Ophthalmology and Visual Science, Nankai University, Tianjin 300000, China
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Ahmad I, Teotia P, Erickson H, Xia X. Recapitulating developmental mechanisms for retinal regeneration. Prog Retin Eye Res 2019; 76:100824. [PMID: 31843569 DOI: 10.1016/j.preteyeres.2019.100824] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 12/06/2019] [Accepted: 12/11/2019] [Indexed: 12/18/2022]
Abstract
Degeneration of specific retinal neurons in diseases like glaucoma, age-related macular degeneration, and retinitis pigmentosa is the leading cause of irreversible blindness. Currently, there is no therapy to modify the disease-associated degenerative changes. With the advancement in our knowledge about the mechanisms that regulate the development of the vertebrate retina, the approach to treat blinding diseases through regenerative medicine appears a near possibility. Recapitulation of developmental mechanisms is critical for reproducibly generating cells in either 2D or 3D culture of pluripotent stem cells for retinal repair and disease modeling. It is the key for unlocking the neurogenic potential of Müller glia in the adult retina for therapeutic regeneration. Here, we examine the current status and potential of the regenerative medicine approach for the retina in the backdrop of developmental mechanisms.
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Affiliation(s)
- Iqbal Ahmad
- Department of Ophthalmology and Visual Science, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
| | - Pooja Teotia
- Department of Ophthalmology and Visual Science, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Helen Erickson
- Department of Ophthalmology and Visual Science, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Xiaohuan Xia
- Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, 200072, China
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14
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Adil MT, Simons CM, Sonam S, Henry JJ. Understanding cornea homeostasis and wound healing using a novel model of stem cell deficiency in Xenopus. Exp Eye Res 2019; 187:107767. [PMID: 31437439 DOI: 10.1016/j.exer.2019.107767] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 07/25/2019] [Accepted: 08/16/2019] [Indexed: 12/13/2022]
Abstract
Limbal Stem Cell Deficiency (LSCD) is a painful and debilitating disease that results from damage or loss of the Corneal Epithelial Stem Cells (CESCs). Therapies have been developed to treat LSCD by utilizing epithelial stem cell transplants. However, effective repair and recovery depends on many factors, such as the source and concentration of donor stem cells, and the proper conditions to support these transplanted cells. We do not yet fully understand how CESCs heal wounds or how transplanted CESCs are able to restore transparency in LSCD patients. A major hurdle has been the lack of vertebrate models to study CESCs. Here we utilized a short treatment with Psoralen AMT (a DNA cross-linker), immediately followed by UV treatment (PUV treatment), to establish a novel frog model that recapitulates the characteristics of cornea stem cell deficiency, such as pigment cell invasion from the periphery, corneal opacity, and neovascularization. These PUV treated whole corneas do not regain transparency. Moreover, PUV treatment leads to appearance of the Tcf7l2 labeled subset of apical skin cells in the cornea region. PUV treatment also results in increased cell death, immediately following treatment, with pyknosis as a primary mechanism. Furthermore, we show that PUV treatment causes depletion of p63 expressing basal epithelial cells, and can stimulate mitosis in the remaining cells in the cornea region. To study the response of CESCs, we created localized PUV damage by focusing the UV radiation on one half of the cornea. These cases initially develop localized stem cell deficiency characteristics on the treated side. The localized PUV treatment is also capable of stimulating some mitosis in the untreated (control) half of those corneas. Unlike the whole treated corneas, the treated half is ultimately able to recover and corneal transparency is restored. Our study provides insight into the response of cornea cells following stem cell depletion, and establishes Xenopus as a suitable model for studying CESCs, stem cell deficiency, and other cornea diseases. This model will also be valuable for understanding the nature of transplanted CESCs, which will lead to progress in the development of therapeutics for LSCD.
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Affiliation(s)
- Mohd Tayyab Adil
- Department of Cell & Developmental Biology, University of Illinois at Urbana-Champaign, 601 S. Goodwin Ave. Urbana, IL, 61801, USA.
| | - Claire M Simons
- Department of Cell & Developmental Biology, University of Illinois at Urbana-Champaign, 601 S. Goodwin Ave. Urbana, IL, 61801, USA.
| | - Surabhi Sonam
- Department of Cell & Developmental Biology, University of Illinois at Urbana-Champaign, 601 S. Goodwin Ave. Urbana, IL, 61801, USA.
| | - Jonathan J Henry
- Department of Cell & Developmental Biology, University of Illinois at Urbana-Champaign, 601 S. Goodwin Ave. Urbana, IL, 61801, USA.
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15
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Harding P, Moosajee M. The Molecular Basis of Human Anophthalmia and Microphthalmia. J Dev Biol 2019; 7:jdb7030016. [PMID: 31416264 PMCID: PMC6787759 DOI: 10.3390/jdb7030016] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 08/08/2019] [Accepted: 08/08/2019] [Indexed: 12/16/2022] Open
Abstract
Human eye development is coordinated through an extensive network of genetic signalling pathways. Disruption of key regulatory genes in the early stages of eye development can result in aborted eye formation, resulting in an absent eye (anophthalmia) or a small underdeveloped eye (microphthalmia) phenotype. Anophthalmia and microphthalmia (AM) are part of the same clinical spectrum and have high genetic heterogeneity, with >90 identified associated genes. By understanding the roles of these genes in development, including their temporal expression, the phenotypic variation associated with AM can be better understood, improving diagnosis and management. This review describes the genetic and structural basis of eye development, focusing on the function of key genes known to be associated with AM. In addition, we highlight some promising avenues of research involving multiomic approaches and disease modelling with induced pluripotent stem cell (iPSC) technology, which will aid in developing novel therapies.
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Affiliation(s)
| | - Mariya Moosajee
- UCL Institute of Ophthalmology, London EC1V 9EL, UK.
- Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK.
- Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
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16
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Cui R, Lwigale P. Expression of the heparin-binding growth factors Midkine and pleiotrophin during ocular development. Gene Expr Patterns 2019; 32:28-37. [PMID: 30825522 DOI: 10.1016/j.gep.2019.02.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 02/18/2019] [Accepted: 02/21/2019] [Indexed: 12/17/2022]
Abstract
Midkine (MDK) and Pleiotrophin (PTN) belong to a group of heparin-binding growth factors that has been shown to have pleiotropic functions in various biological processes during development and disease. Development of the vertebrate eye is a multistep process that involves coordinated interactions between neuronal and non-neuronal cells, but very little is known about the potential function of MDK and PTN in these processes. In this study, we demonstrate by section in situ hybridization, the spatiotemporal expression of MDK and PTN during ocular development in chick and mouse. We show that MDK and PTN are expressed in dynamic patterns that overlap in a few non-neuronal tissues in the anterior eye and in neuronal cell layers of the posterior eye. We show that the expression patterns of MDK and PTN are only conserved in a few tissues in chick and mouse but they overlap with the expression of some of their receptors LRP1, RPTPZ, ALK, NOTCH2, ITGβ1, SDC1, and SDC3. The dynamic expression patterns of MDK, PTN and their receptors suggest that they function together during the multistep process of ocular development and they may play important roles in cell proliferation, adhesion, and migration of neuronal and non-neuronal cells.
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Affiliation(s)
- Ruda Cui
- Department of BioSciences, Rice University, Houston, TX, USA
| | - Peter Lwigale
- Department of BioSciences, Rice University, Houston, TX, USA.
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17
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Pluripotent Stem Cells as Models of Retina Development. Mol Neurobiol 2019; 56:6056-6070. [DOI: 10.1007/s12035-019-1504-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 01/21/2019] [Indexed: 01/01/2023]
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18
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Abstract
This chapter provides an overview of the early developmental origins of six ocular tissues: the cornea, lens, ciliary body, iris, neural retina, and retina pigment epithelium. Many of these tissue types are concurrently specified and undergo a complex set of morphogenetic movements that facilitate their structural interconnection. Within the context of vertebrate eye organogenesis, we also discuss the genetic hierarchies of transcription factors and signaling pathways that regulate growth, patterning, cell type specification and differentiation.
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Affiliation(s)
- Joel B Miesfeld
- Department of Cell Biology & Human Anatomy, University of California Davis School of Medicine, Davis, CA, United States
| | - Nadean L Brown
- Department of Cell Biology & Human Anatomy, University of California Davis School of Medicine, Davis, CA, United States.
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19
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Bovolenta P, Martinez-Morales JR. Genetics of congenital eye malformations: insights from chick experimental embryology. Hum Genet 2018; 138:1001-1006. [PMID: 29980841 DOI: 10.1007/s00439-018-1900-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Accepted: 06/26/2018] [Indexed: 12/27/2022]
Abstract
Embryological manipulations in chick embryos have been pivotal in our understanding of many aspects of vertebrate eye formation. This research was particularly important in uncovering the role of tissue interactions as drivers of eye morphogenesis and to dissect the function of critical genes. Here, we have highlighted a few of these past experiments to endorse their value in searching for hitherto unknown causes of rare congenital eye anomalies, such as microphthalmia, anophthalmia and coloboma. We have also highlighted a number of similarities between the chicken and human eye, which might be exploited to address other eye pathologies, including degenerative ocular diseases.
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Affiliation(s)
- Paola Bovolenta
- Centro de Biología Molecular "Severo Ochoa," (CSIC/UAM), 28049, Madrid, Spain.
- CIBERER, ISCIII, 28049, Madrid, Spain.
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20
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Bernstein CS, Anderson MT, Gohel C, Slater K, Gross JM, Agarwala S. The cellular bases of choroid fissure formation and closure. Dev Biol 2018; 440:137-151. [PMID: 29803644 DOI: 10.1016/j.ydbio.2018.05.010] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 04/30/2018] [Accepted: 05/14/2018] [Indexed: 01/11/2023]
Abstract
Defects in choroid fissure (CF) formation and closure lead to coloboma, a major cause of childhood blindness. Despite genetic advances, the cellular defects underlying coloboma remain poorly elucidated due to our limited understanding of normal CF morphogenesis. We address this deficit by conducting high-resolution spatio-temporal analyses of CF formation and closure in the chick, mouse and fish. We show that a small ventral midline invagination initiates CF formation in the medial-proximal optic cup, subsequently extending it dorsally toward the lens, and proximally into the optic stalk. Unlike previously supposed, the optic disc does not form solely as a result of this invagination. Morphogenetic events that alter the shape of the proximal optic cup also direct clusters of outer layer and optic stalk cells to form dorsal optic disc. A cross-species comparison suggests that CF closure can be accomplished by breaking down basement membranes (BM) along the CF margins, and by establishing BM continuity along the dorsal and ventral surfaces of the CF. CF closure is subsequently accomplished via two distinct mechanisms: tissue fusion or the intercalation of various tissues into the inter-CF space. We identify several novel cell behaviors that underlie CF fusion, many of which involve remodeling of the retinal epithelium. In addition to BM disruption, these include NCAD downregulation along the SOX2+ retinal CF margin, and the protrusion or movement of partially polarized retinal cells into the inter-CF space to mediate fusion. Proximally, the inter-CF space does not fuse or narrow and is instead loosely packed with migrating SOX2+/PAX2+/Vimentin+ astrocytes until it is closed by the outgoing optic nerve. Taken together, our results highlight distinct proximal-distal differences in CF morphogenesis and closure and establish detailed cellular models that can be utilized for understanding the genetic bases of coloboma.
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Affiliation(s)
- Cassidy S Bernstein
- Molecular Biosciences Department, University of Texas at Austin, Austin, TX 78712, USA
| | - Mitchell T Anderson
- Molecular Biosciences Department, University of Texas at Austin, Austin, TX 78712, USA
| | - Chintan Gohel
- Molecular Biosciences Department, University of Texas at Austin, Austin, TX 78712, USA
| | - Kayleigh Slater
- Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Jeffrey M Gross
- Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Seema Agarwala
- Molecular Biosciences Department, University of Texas at Austin, Austin, TX 78712, USA; Institute for Cell and Molecular Biology, University of Texas at Austin, TX 78712, USA; Institute for Neuroscience, University of Texas at Austin, Austin, TX 78712, USA.
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21
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Lewis RM, Keller JJ, Wan L, Stone JS. Bone morphogenetic protein 4 antagonizes hair cell regeneration in the avian auditory epithelium. Hear Res 2018; 364:1-11. [PMID: 29754876 DOI: 10.1016/j.heares.2018.04.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Revised: 03/11/2018] [Accepted: 04/16/2018] [Indexed: 02/01/2023]
Abstract
Permanent hearing loss is often a result of damage to cochlear hair cells, which mammals are unable to regenerate. Non-mammalian vertebrates such as birds replace damaged hair cells and restore hearing function, but mechanisms controlling regeneration are not understood. The secreted protein bone morphogenetic protein 4 (BMP4) regulates inner ear morphogenesis and hair cell development. To investigate mechanisms controlling hair cell regeneration in birds, we examined expression and function of BMP4 in the auditory epithelia (basilar papillae) of chickens of either sex after hair cell destruction by ototoxic antibiotics. In mature basilar papillae, BMP4 mRNA is highly expressed in hair cells, but not in hair cell progenitors (supporting cells). Supporting cells transcribe genes encoding receptors for BMP4 (BMPR1A, BMPR1B, and BMPR2) and effectors of BMP4 signaling (ID transcription factors). Following hair cell destruction, BMP4 transcripts are lost from the sensory epithelium. Using organotypic cultures, we demonstrate that treatments with BMP4 during hair cell destruction prevent supporting cells from upregulating expression of the pro-hair cell transcription factor ATOH1, entering the cell cycle, and fully transdifferentiating into hair cells, but they do not induce cell death. By contrast, noggin, a BMP4 inhibitor, increases numbers of regenerated hair cells. These findings demonstrate that BMP4 antagonizes hair cell regeneration in the chicken basilar papilla, at least in part by preventing accumulation of ATOH1 in hair cell precursors.
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Affiliation(s)
- Rebecca M Lewis
- University of Washington School of Medicine and the Virginia Merrill Bloedel Hearing Research Center, Seattle, WA, United States; Eaton Peabody Laboratories, Department of Otolaryngology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, United States
| | - Jesse J Keller
- University of Washington School of Medicine and the Virginia Merrill Bloedel Hearing Research Center, Seattle, WA, United States; Oregon Health Sciences University, Portland, OR, United States
| | - Liangcai Wan
- University of Washington School of Medicine and the Virginia Merrill Bloedel Hearing Research Center, Seattle, WA, United States; Department of Otolaryngology-Head and Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jennifer S Stone
- University of Washington School of Medicine and the Virginia Merrill Bloedel Hearing Research Center, Seattle, WA, United States.
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22
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How mechanical forces shape the developing eye. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2018; 137:25-36. [PMID: 29432780 DOI: 10.1016/j.pbiomolbio.2018.01.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 01/08/2018] [Accepted: 01/15/2018] [Indexed: 12/29/2022]
Abstract
In the vertebrate embryo, the eyes develop from optic vesicles that grow laterally outward from the brain tube and contact the overlying surface ectoderm. Within the region of contact, each optic vesicle and the surface ectoderm thicken to form placodes, which then invaginate to create the optic cup and lens pit, respectively. Eventually, the optic cup becomes the retina, while the lens pit closes to form the lens vesicle. Here, we review current hypotheses for the physical mechanisms that create these structures and present novel three-dimensional computer (finite-element) models to illustrate the plausibility and limitations of these hypotheses. Taken together, experimental and numerical results suggest that the driving forces for early eye morphogenesis are generated mainly by differential growth, actomyosin contraction, and regional apoptosis, with morphology mediated by physical constraints provided by adjacent tissues and extracellular matrix. While these studies offer new insight into the mechanics of eye development, future work is needed to better understand how these mechanisms are regulated to precisely control the shape of the eye.
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23
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Llonch S, Carido M, Ader M. Organoid technology for retinal repair. Dev Biol 2017; 433:132-143. [PMID: 29291970 DOI: 10.1016/j.ydbio.2017.09.028] [Citation(s) in RCA: 115] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 09/05/2017] [Accepted: 09/21/2017] [Indexed: 02/07/2023]
Abstract
A major cause for vision impairment and blindness in industrialized countries is the loss of the light-sensing retinal tissue in the eye. Photoreceptor damage is one of the main characteristics found in retinal degeneration diseases, such as Retinitis Pigmentosa or age-related macular degeneration. The lack of effective therapies to stop photoreceptor loss together with the absence of significant intrinsic regeneration in the human retina converts such degenerative diseases into permanent conditions that are currently irreversible. Cell replacement by means of photoreceptor transplantation has been proposed as a potential approach to tackle cell loss in the retina. Since the first attempt of photoreceptor transplantation in humans, about twenty years ago, several research groups have focused in the development and improvement of technologies necessary to bring cell transplantation for retinal degeneration diseases to reality. Progress in recent years in the generation of human tissue derived from pluripotent stem cells (PSCs) has significantly improved our tools to study human development and disease in the dish. Particularly the availability of 3D culture systems for the generation of PSC-derived organoids, including the human retina, has dramatically increased access to human material for basic and medical research. In this review, we focus on important milestones towards the generation of transplantable photoreceptor precursors from PSC-derived retinal organoids and discuss recent pre-clinical transplantation studies using organoid-derived photoreceptors in context to related in vivo work using primary photoreceptors as donor material. Additionally, we summarize remaining challenges for developing photoreceptor transplantation towards clinical application.
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Affiliation(s)
- Sílvia Llonch
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany
| | - Madalena Carido
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany; German Center for Neurodegenerative Diseases Dresden (DZNE), Arnoldstraße 18, 01307 Dresden, Germany
| | - Marius Ader
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany.
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24
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Martinez-Morales JR, Cavodeassi F, Bovolenta P. Coordinated Morphogenetic Mechanisms Shape the Vertebrate Eye. Front Neurosci 2017; 11:721. [PMID: 29326547 PMCID: PMC5742352 DOI: 10.3389/fnins.2017.00721] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 12/11/2017] [Indexed: 11/22/2022] Open
Abstract
The molecular bases of vertebrate eye formation have been extensively investigated during the past 20 years. This has resulted in the definition of the backbone of the gene regulatory networks controlling the different steps of eye development and has further highlighted a substantial conservation of these networks among vertebrates. Yet, the precise morphogenetic events allowing the formation of the optic cup from a small group of cells within the anterior neural plate are still poorly understood. It is also unclear if the morphogenetic events leading to eyes of very similar shape are indeed comparable among all vertebrates or if there are any species-specific peculiarities. Improved imaging techniques have enabled to follow how the eye forms in living embryos of a few vertebrate models, whereas the development of organoid cultures has provided fascinating tools to recapitulate tissue morphogenesis of other less accessible species. Here, we will discuss what these advances have taught us about eye morphogenesis, underscoring possible similarities and differences among vertebrates. We will also discuss the contribution of cell shape changes to this process and how morphogenetic and patterning mechanisms integrate to assemble the final architecture of the eye.
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Affiliation(s)
| | - Florencia Cavodeassi
- Centro de Biología Molecular Severo Ochoa, (CSIC/UAM), Madrid, Spain.,CIBERER, ISCIII, Madrid, Spain
| | - Paola Bovolenta
- Centro de Biología Molecular Severo Ochoa, (CSIC/UAM), Madrid, Spain.,CIBERER, ISCIII, Madrid, Spain
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25
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Nogueira RC, Sampaio LDFS. Eye and heart morphogenesis are dependent on melatonin signaling in chick embryos. ACTA ACUST UNITED AC 2017; 220:3826-3835. [PMID: 28839011 DOI: 10.1242/jeb.159848] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 08/18/2017] [Indexed: 12/15/2022]
Abstract
Calmodulin is vital for chick embryos morphogenesis in the incubation time 48-66 h when the rudimentary C-shaped heart attains an S-shaped pattern and the optic vesicles develop into optic cups. Melatonin is in the extraembryonic yolk sac of the avian egg; melatonin binds calmodulin. The aim of this study was to investigate the function of melatonin in the formation of the chick embryo optic cups and S-shaped heart, by pharmacological methods and immunoassays. Mel1a melatonin receptor immunofluorescence was distributed in the optic cups and rudimentary hearts. We separated embryonated chicken eggs at 48 h of incubation into basal, control and drug-treated groups, with treatment applied in the egg air sac. At 66 h of incubation, embryos were excised from the eggs and analyzed. Embryos from the basal, control (distilled water), melatonin and 6-chloromelatonin (melatonin receptor agonist) groups had regular optic cups and an S-shaped heart, while those from the calmidazolium (calmodulin inhibitor) group did not. Embryos from the luzindole (melatonin receptor antagonist) and prazosin (Mel1c melatonin receptor antagonist) groups did not have regular optic cups. Embryos from the 4-P-PDOT (Mel1b melatonin receptor antagonist) group did not have an S-shaped heart. Previous application of the melatonin, 6-chloromelatonin or forskolin (adenylate cyclase enhancer) prevented the abnormal appearance of chick embryos from the calmidazolium, luzindole, prazosin and 4-P-PDOT groups. However, 6-chloromelatonin and forskolin only partially prevented the development of defective eye cups in embryos from the calmidazolium group. The results suggested that melatonin modulates chick embryo morphogenesis via calmodulin and membrane receptors.
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Affiliation(s)
- Renato C Nogueira
- Laboratório de Bioquímica do Desenvolvimento do Sistema Nervoso, Instituto de Ciências Biológicas, Universidade Federal do Pará. Av. Augusto Corrêa 1, CEP: 66075-110 Belém, PA, Brazil
| | - Lucia de Fatima S Sampaio
- Laboratório de Bioquímica do Desenvolvimento do Sistema Nervoso, Instituto de Ciências Biológicas, Universidade Federal do Pará. Av. Augusto Corrêa 1, CEP: 66075-110 Belém, PA, Brazil
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26
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Weed LS, Mills JA. Strategies for retinal cell generation from human pluripotent stem cells. Stem Cell Investig 2017; 4:65. [PMID: 28815176 DOI: 10.21037/sci.2017.07.02] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 05/24/2017] [Indexed: 12/22/2022]
Abstract
Induced pluripotent stem cells (iPSCs) are specialized self-renewing cells that are generated by exogenously expressing pluripotency-associated transcription factors in somatic cells such as fibroblasts, peripheral blood mononuclear cells, or lymphoblastoid cell lines (LCLs). iPSCs are functionally similar to naturally pluripotent embryonic stem cells (ESCs) in their capacity to propagate indefinitely and potential to differentiate into all human cell types, and are devoid of the associated ethical complications of origin. iPSCs are useful for studying embryonic development, disease modeling, and drug screening. Additionally, iPSCs provide a personalized approach for pathological studies, particularly for diseases that lack appropriate animal models. Retinal cell differentiations using iPSCs have been successful in this regard. Several protocols to generate various retinal cells have been developed to maximize a specific cell type or, most recently, to mimic in vivo retinal structure and cellular environment. As differentiation protocols continue to improve we are likely to see an increase in our basic understanding of various retinal degenerative diseases and the utilization of iPSCs in clinical trials.
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Affiliation(s)
- Lindsey S Weed
- Center for Advanced Retinal and Ocular Therapeutics, F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Jason A Mills
- Center for Advanced Retinal and Ocular Therapeutics, F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
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27
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Steinfeld J, Steinfeld I, Bausch A, Coronato N, Hampel ML, Depner H, Layer PG, Vogel-Höpker A. BMP-induced reprogramming of the neural retina into retinal pigment epithelium requires Wnt signalling. Biol Open 2017; 6:979-992. [PMID: 28546339 PMCID: PMC5550904 DOI: 10.1242/bio.018739] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 05/21/2017] [Indexed: 12/13/2022] Open
Abstract
In vertebrates, the retinal pigment epithelium (RPE) and photoreceptors of the neural retina (NR) comprise a functional unit required for vision. During vertebrate eye development, a conversion of the RPE into NR can be induced by growth factors in vivo at optic cup stages, but the reverse process, the conversion of NR tissue into RPE, has not been reported. Here, we show that bone morphogenetic protein (BMP) signalling can reprogram the NR into RPE at optic cup stages in chick. Shortly after BMP application, expression of Microphthalmia-associated transcription factor (Mitf) is induced in the NR and selective cell death on the basal side of the NR induces an RPE-like morphology. The newly induced RPE differentiates and expresses Melanosomalmatrix protein 115 (Mmp115) and RPE65. BMP-induced Wnt2b expression is observed in regions of the NR that become pigmented. Loss of function studies show that conversion of the NR into RPE requires both BMP and Wnt signalling. Simultaneous to the appearance of ectopic RPE tissue, BMP application reprogrammed the proximal RPE into multi-layered retinal tissue. The newly induced NR expresses visual segment homeobox-containing gene (Vsx2), and the ganglion and photoreceptor cell markers Brn3α and Visinin are detected. Our results show that high BMP concentrations are required to induce the conversion of NR into RPE, while low BMP concentrations can still induce transdifferentiation of the RPE into NR. This knowledge may contribute to the development of efficient standardized protocols for RPE and NR generation for cell replacement therapies.
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Affiliation(s)
- Jörg Steinfeld
- Fachbereich Biologie, Abteilung Stammzell- und Entwicklungsbiologie, Schnittspahnstraße 13, Darmstadt 64287, Germany
| | - Ichie Steinfeld
- Fachbereich Biologie, Abteilung Stammzell- und Entwicklungsbiologie, Schnittspahnstraße 13, Darmstadt 64287, Germany
| | - Alexander Bausch
- Fachbereich Biologie, Abteilung Stammzell- und Entwicklungsbiologie, Schnittspahnstraße 13, Darmstadt 64287, Germany
| | - Nicola Coronato
- Fachbereich Biologie, Abteilung Stammzell- und Entwicklungsbiologie, Schnittspahnstraße 13, Darmstadt 64287, Germany
| | - Meggi-Lee Hampel
- Fachbereich Biologie, Abteilung Stammzell- und Entwicklungsbiologie, Schnittspahnstraße 13, Darmstadt 64287, Germany
| | - Heike Depner
- Fachbereich Biologie, Abteilung Stammzell- und Entwicklungsbiologie, Schnittspahnstraße 13, Darmstadt 64287, Germany
| | - Paul G Layer
- Fachbereich Biologie, Abteilung Stammzell- und Entwicklungsbiologie, Schnittspahnstraße 13, Darmstadt 64287, Germany
| | - Astrid Vogel-Höpker
- Fachbereich Biologie, Abteilung Stammzell- und Entwicklungsbiologie, Schnittspahnstraße 13, Darmstadt 64287, Germany
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Iida H, Yang T, Yasugi S, Ishii Y. Temporal dissociation of developmental events in the chick eye under low temperature conditions. Dev Growth Differ 2016; 58:741-749. [PMID: 27921294 DOI: 10.1111/dgd.12330] [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: 11/05/2016] [Revised: 11/08/2016] [Accepted: 11/08/2016] [Indexed: 11/28/2022]
Abstract
The chick embryonic eye is an excellent model for the study of vertebrate organogenesis. Key events in eye development involve thickening, invagination and cytodifferentiation of the lens primordium. While these events occur successively at different developmental stages, the extent to which these events are temporally related is largely unknown. Here we show that the lens invagination is highly sensitive to temperature. Lowering of incubation temperature to 29°C at embryonic day 2 delayed the onset of invagination of the lens, but not thickening and cytodifferentiation, leading to abnormal protrusion of the eye. The temperature shift also delayed the inward bending of the underlying retinal primordium, even in the absence of the lens. Taken together, our results suggest that lens invagination is initiated independently of thickening and cytodifferentiation, possibly by mechanisms associated with morphogenesis of the primordial retina.
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Affiliation(s)
- Hideaki Iida
- Department of Biotechnology, Faculty of Engineering, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-ku, Kyoto, 603-8555, Japan
| | - Tiantian Yang
- Department of Biotechnology, Faculty of Engineering, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-ku, Kyoto, 603-8555, Japan
| | - Sadao Yasugi
- Department of Biotechnology, Faculty of Engineering, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-ku, Kyoto, 603-8555, Japan.,Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-ku, Kyoto, 603-8555, Japan
| | - Yasuo Ishii
- Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-ku, Kyoto, 603-8555, Japan
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29
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Requirement of Smad4 from Ocular Surface Ectoderm for Retinal Development. PLoS One 2016; 11:e0159639. [PMID: 27494603 PMCID: PMC4975478 DOI: 10.1371/journal.pone.0159639] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 07/06/2016] [Indexed: 11/28/2022] Open
Abstract
Microphthalmia is characterized by abnormally small eyes and usually retinal dysplasia, accounting for up to 11% of the blindness in children. Right now there is no effective treatment for the disease, and the underlying mechanisms, especially how retinal dysplasia develops from microphthalmia and whether it depends on the signals from lens ectoderm are still unclear. Mutations in genes of the TGF-β superfamily have been noted in patients with microphthalmia. Using conditional knockout mice, here we address the question that whether ocular surface ectoderm-derived Smad4 modulates retinal development. We found that loss of Smad4 specifically on surface lens ectoderm leads to microphthalmia and dysplasia of retina. Retinal dysplasia in the knockout mice is caused by the delayed or failed differentiation and apoptosis of retinal cells. Microarray analyses revealed that members of Hedgehog and Wnt signaling pathways are affected in the knockout retinas, suggesting that ocular surface ectoderm-derived Smad4 can regulate Hedgehog and Wnt signaling in the retina. Our studies suggest that defective of ocular surface ectoderm may affect retinal development.
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30
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Anand D, Lachke SA. Systems biology of lens development: A paradigm for disease gene discovery in the eye. Exp Eye Res 2016; 156:22-33. [PMID: 26992779 DOI: 10.1016/j.exer.2016.03.010] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Revised: 03/08/2016] [Accepted: 03/11/2016] [Indexed: 12/19/2022]
Abstract
Over the past several decades, the biology of the developing lens has been investigated using molecular genetics-based approaches in various vertebrate model systems. These efforts, involving target gene knockouts or knockdowns, have led to major advances in our understanding of lens morphogenesis and the pathological basis of cataracts, as well as of other lens related eye defects. In particular, we now have a functional understanding of regulators such as Pax6, Six3, Sox2, Oct1 (Pou2f1), Meis1, Pnox1, Zeb2 (Sip1), Mab21l1, Foxe3, Tfap2a (Ap2-alpha), Pitx3, Sox11, Prox1, Sox1, c-Maf, Mafg, Mafk, Hsf4, Fgfrs, Bmp7, and Tdrd7 in this tissue. However, whether these individual regulators interact or their targets overlap, and the significance of such interactions during lens morphogenesis, is not well defined. The arrival of high-throughput approaches for gene expression profiling (microarrays, RNA-sequencing (RNA-seq), etc.), which can be coupled with chromatin immunoprecipitation (ChIP) or RNA immunoprecipitation (RIP) assays, along with improved computational resources and publically available datasets (e.g. those containing comprehensive protein-protein, protein-DNA information), presents new opportunities to advance our understanding of the lens tissue on a global systems level. Such systems-level knowledge will lead to the derivation of the underlying lens gene regulatory network (GRN), defined as a circuit map of the regulator-target interactions functional in lens development, which can be applied to expedite cataract gene discovery. In this review, we cover the various systems-level approaches such as microarrays, RNA-seq, and ChIP that are already being applied to lens studies and discuss strategies for assembling and interpreting these vast amounts of high-throughput information for effective dispersion to the scientific community. In particular, we discuss strategies for effective interpretation of this new information in the context of the rich knowledge obtained through the application of traditional single-gene focused experiments on the lens. Finally, we discuss our vision for integrating these diverse high-throughput datasets in a single web-based user-friendly tool iSyTE (integrated Systems Tool for Eye gene discovery) - a resource that is already proving effective in the identification and characterization of genes linked to lens development and cataract. We anticipate that application of a similar approach to other ocular tissues such as the retina and the cornea, and even other organ systems, will significantly impact disease gene discovery.
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Affiliation(s)
- Deepti Anand
- Department of Biological Sciences, University of Delaware, Newark, DE, USA
| | - Salil A Lachke
- Department of Biological Sciences, University of Delaware, Newark, DE, USA; Center for Bioinformatics and Computational Biology, University of Delaware, Newark, DE, USA.
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31
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Oltean A, Huang J, Beebe DC, Taber LA. Tissue growth constrained by extracellular matrix drives invagination during optic cup morphogenesis. Biomech Model Mechanobiol 2016; 15:1405-1421. [PMID: 26984743 DOI: 10.1007/s10237-016-0771-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Accepted: 02/05/2016] [Indexed: 12/19/2022]
Abstract
In the early embryo, the eyes form initially as relatively spherical optic vesicles (OVs) that protrude from both sides of the brain tube. Each OV grows until it contacts and adheres to the overlying surface ectoderm (SE) via an extracellular matrix (ECM) that is secreted by the SE and OV. The OV and SE then thicken and bend inward (invaginate) to create the optic cup (OC) and lens vesicle, respectively. While constriction of cell apices likely plays a role in SE invagination, the mechanisms that drive OV invagination are poorly understood. Here, we used experiments and computational modeling to explore the hypothesis that the ECM locally constrains the growing OV, forcing it to invaginate. In chick embryos, we examined the need for the ECM by (1) removing SE at different developmental stages and (2) exposing the embryo to collagenase. At relatively early stages of invagination (Hamburger-Hamilton stage HH14[Formula: see text]), removing the SE caused the curvature of the OV to reverse as it 'popped out' and became convex, but the OV remained concave at later stages (HH15) and invaginated further during subsequent culture. Disrupting the ECM had a similar effect, with the OV popping out at early to mid-stages of invagination (HH14[Formula: see text] to HH14[Formula: see text]). These results suggest that the ECM is required for the early stages but not the late stages of OV invagination. Microindentation tests indicate that the matrix is considerably stiffer than the cellular OV, and a finite-element model consisting of a growing spherical OV attached to a relatively stiff layer of ECM reproduced the observed behavior, as well as measured temporal changes in OV curvature, wall thickness, and invagination depth reasonably well. Results from our study also suggest that the OV grows relatively uniformly, while the ECM is stiffer toward the center of the optic vesicle. These results are consistent with our matrix-constraint hypothesis, providing new insight into the mechanics of OC (early retina) morphogenesis.
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Affiliation(s)
- Alina Oltean
- Department of Biomedical Engineering, Washington University, One Brookings Drive, Campus Box 1097, Saint Louis, MO, 63130-4899, USA.
| | - Jie Huang
- Department of Ophthalmology and Visual Sciences, Washington University, Saint Louis, MO, 63130, USA
| | - David C Beebe
- Department of Ophthalmology and Visual Sciences, Washington University, Saint Louis, MO, 63130, USA
| | - Larry A Taber
- Department of Biomedical Engineering, Washington University, One Brookings Drive, Campus Box 1097, Saint Louis, MO, 63130-4899, USA
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32
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Suzuki IK, Vanderhaeghen P. Is this a brain which I see before me? Modeling human neural development with pluripotent stem cells. Development 2016; 142:3138-50. [PMID: 26395142 DOI: 10.1242/dev.120568] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The human brain is arguably the most complex structure among living organisms. However, the specific mechanisms leading to this complexity remain incompletely understood, primarily because of the poor experimental accessibility of the human embryonic brain. Over recent years, technologies based on pluripotent stem cells (PSCs) have been developed to generate neural cells of various types. While the translational potential of PSC technologies for disease modeling and/or cell replacement therapies is usually put forward as a rationale for their utility, they are also opening novel windows for direct observation and experimentation of the basic mechanisms of human brain development. PSC-based studies have revealed that a number of cardinal features of neural ontogenesis are remarkably conserved in human models, which can be studied in a reductionist fashion. They have also revealed species-specific features, which constitute attractive lines of investigation to elucidate the mechanisms underlying the development of the human brain, and its link with evolution.
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Affiliation(s)
- Ikuo K Suzuki
- Université Libre de Bruxelles (ULB), Institute for Interdisciplinary Research (IRIBHM), and ULB Institute of Neuroscience (UNI), 808 Route de Lennik, Brussels B-1070, Belgium
| | - Pierre Vanderhaeghen
- Université Libre de Bruxelles (ULB), Institute for Interdisciplinary Research (IRIBHM), and ULB Institute of Neuroscience (UNI), 808 Route de Lennik, Brussels B-1070, Belgium WELBIO, Université Libre de Bruxelles, 808 Route de Lennik, Brussels B-1070, Belgium
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33
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Huang J, Liu Y, Filas B, Gunhaga L, Beebe DC. Negative and positive auto-regulation of BMP expression in early eye development. Dev Biol 2015; 407:256-64. [PMID: 26407529 DOI: 10.1016/j.ydbio.2015.09.009] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 09/08/2015] [Accepted: 09/15/2015] [Indexed: 02/09/2023]
Abstract
Previous results have shown that Bone Morphogenetic Protein (BMP) signaling is essential for lens specification and differentiation. How BMP signals are regulated in the prospective lens ectoderm is not well defined. To address this issue we have modulated BMP activity in a chicken embryo pre-lens ectoderm explant assay, and also studied transgenic mice, in which the type I BMP receptors, Bmpr1a and Acvr1, are deleted from the prospective lens ectoderm. Our results show that chicken embryo pre-lens ectoderm cells express BMPs and require BMP signaling for lens specification in vitro, and that in vivo inhibition of BMP signals in the mouse prospective lens ectoderm interrupts lens placode formation and prevents lens invagination. Furthermore, our results provide evidence that BMP expression is negatively auto-regulated in the lens-forming ectoderm, decreasing when the tissue is exposed to exogenous BMPs and increasing when BMP signaling is prevented. In addition, eyes lacking BMP receptors in the prospective lens placode develop coloboma in the adjacent wild type optic cup. In these eyes, Bmp7 expression increases in the ventral optic cup and the normal dorsal-ventral gradient of BMP signaling in the optic cup is disrupted. Pax2 becomes undetectable and expression of Sfrp2 increases in the ventral optic cup, suggesting that increased BMP signaling alter their expression, resulting in failure to close the optic fissure. In summary, our results suggest that negative and positive auto-regulation of BMP expression is important to regulate early eye development.
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Affiliation(s)
- Jie Huang
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA.
| | - Ying Liu
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA
| | - Benjamen Filas
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA
| | - Lena Gunhaga
- Umeå Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - David C Beebe
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA
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34
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Pandit T, Jidigam VK, Patthey C, Gunhaga L. Neural retina identity is specified by lens-derived BMP signals. Development 2015; 142:1850-9. [PMID: 25968316 PMCID: PMC4440930 DOI: 10.1242/dev.123653] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The eye has served as a classical model to study cell specification and tissue induction for over a century. Nevertheless, the molecular mechanisms that regulate the induction and maintenance of eye-field cells, and the specification of neural retina cells are poorly understood. Moreover, within the developing anterior forebrain, how prospective eye and telencephalic cells are differentially specified is not well defined. In the present study, we have analyzed these issues by manipulating signaling pathways in intact chick embryo and explant assays. Our results provide evidence that at blastula stages, BMP signals inhibit the acquisition of eye-field character, but from neural tube/optic vesicle stages, BMP signals from the lens are crucial for the maintenance of eye-field character, inhibition of dorsal telencephalic cell identity and specification of neural retina cells. Subsequently, our results provide evidence that a Rax2-positive eye-field state is not sufficient for the progress to a neural retina identity, but requires BMP signals. In addition, our results argue against any essential role of Wnt or FGF signals during the specification of neural retina cells, but provide evidence that Wnt signals together with BMP activity are sufficient to induce cells of retinal pigment epithelial character. We conclude that BMP activity emanating from the lens ectoderm maintains eye-field identity, inhibits telencephalic character and induces neural retina cells. Our findings link the requirement of the lens ectoderm for neural retina specification with the molecular mechanism by which cells in the forebrain become specified as neural retina by BMP activity. SUMMARY: BMP signals from the lens are crucial to maintain eye-field character, inhibit dorsal telencephalic cell identity, and specificy neural retina cells in chick embryos.
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Affiliation(s)
- Tanushree Pandit
- Umeå Centre for Molecular Medicine, Umeå University, Umeå 901 87, Sweden
| | - Vijay K Jidigam
- Umeå Centre for Molecular Medicine, Umeå University, Umeå 901 87, Sweden
| | - Cedric Patthey
- Umeå Centre for Molecular Medicine, Umeå University, Umeå 901 87, Sweden
| | - Lena Gunhaga
- Umeå Centre for Molecular Medicine, Umeå University, Umeå 901 87, Sweden
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35
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Mellough CB, Collin J, Khazim M, White K, Sernagor E, Steel DHW, Lako M. IGF-1 Signaling Plays an Important Role in the Formation of Three-Dimensional Laminated Neural Retina and Other Ocular Structures From Human Embryonic Stem Cells. Stem Cells 2015; 33:2416-30. [PMID: 25827910 PMCID: PMC4691326 DOI: 10.1002/stem.2023] [Citation(s) in RCA: 113] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 03/11/2015] [Indexed: 12/17/2022]
Abstract
We and others have previously demonstrated that retinal cells can be derived from human embryonic stem cells (hESCs) and induced pluripotent stem cells under defined culture conditions. While both cell types can give rise to retinal derivatives in the absence of inductive cues, this requires extended culture periods and gives lower overall yield. Further understanding of this innate differentiation ability, the identification of key factors that drive the differentiation process, and the development of clinically compatible culture conditions to reproducibly generate functional neural retina is an important goal for clinical cell based therapies. We now report that insulin-like growth factor 1 (IGF-1) can orchestrate the formation of three-dimensional ocular-like structures from hESCs which, in addition to retinal pigmented epithelium and neural retina, also contain primitive lens and corneal-like structures. Inhibition of IGF-1 receptor signaling significantly reduces the formation of optic vesicle and optic cups, while exogenous IGF-1 treatment enhances the formation of correctly laminated retinal tissue composed of multiple retinal phenotypes that is reminiscent of the developing vertebrate retina. Most importantly, hESC-derived photoreceptors exhibit advanced maturation features such as the presence of primitive rod- and cone-like photoreceptor inner and outer segments and phototransduction-related functional responses as early as 6.5 weeks of differentiation, making these derivatives promising candidates for cell replacement studies and in vitro disease modeling.
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Affiliation(s)
- Carla B. Mellough
- Institute of Genetic MedicineNewcastle UniversityNewcastleUnited Kingdom
| | - Joseph Collin
- Institute of Genetic MedicineNewcastle UniversityNewcastleUnited Kingdom
| | - Mahmoud Khazim
- Institute of Genetic MedicineNewcastle UniversityNewcastleUnited Kingdom
- Institute of NeuroscienceNewcastle UniversityNewcastleUnited Kingdom
| | - Kathryn White
- EM Research Services, Newcastle UniversityNewcastleUnited Kingdom
| | - Evelyne Sernagor
- Institute of NeuroscienceNewcastle UniversityNewcastleUnited Kingdom
| | - David H. W. Steel
- Institute of Genetic MedicineNewcastle UniversityNewcastleUnited Kingdom
- Sunderland Eye InfirmarySunderlandUnited Kingdom
| | - Majlinda Lako
- Institute of Genetic MedicineNewcastle UniversityNewcastleUnited Kingdom
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36
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Gago-Rodrigues I, Fernández-Miñán A, Letelier J, Naranjo S, Tena JJ, Gómez-Skarmeta JL, Martinez-Morales JR. Analysis of opo cis-regulatory landscape uncovers Vsx2 requirement in early eye morphogenesis. Nat Commun 2015; 6:7054. [DOI: 10.1038/ncomms8054] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 03/26/2015] [Indexed: 11/09/2022] Open
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Huang J, Liu Y, Oltean A, Beebe DC. Bmp4 from the optic vesicle specifies murine retina formation. Dev Biol 2015; 402:119-26. [PMID: 25792196 DOI: 10.1016/j.ydbio.2015.03.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 03/06/2015] [Accepted: 03/07/2015] [Indexed: 01/30/2023]
Abstract
Previous studies of mouse embryos concluded that after the optic vesicle evaginates from the ventral forebrain and contacts the surface ectoderm, signals from the ectoderm specify the distal region of the optic vesicle to become retina and signals from the optic vesicle induce the lens. Germline deletion of Bmp4 resulted in failure of lens formation. We performed conditional deletion of Bmp4 from the optic vesicle to test the function of Bmp4 in murine eye development. The optic vesicle evaginated normally and contacted the surface ectoderm. Lens induction did not occur. The optic cup failed to form and the expression of retina-specific genes decreased markedly in the distal optic vesicle. Instead, cells in the prospective retina expressed genes characteristic of the retinal pigmented epithelium. We conclude that Bmp4 is required for retina specification in mice. In the absence of Bmp4, formation of the retinal pigmented epithelium is the default differentiation pathway of the optic vesicle. Differences in the signaling pathways required for specification of the retina and retinal pigmented epithelium in chicken and mouse embryos suggest major changes in signaling during the evolution of the vertebrate eye.
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Affiliation(s)
- Jie Huang
- Department of Ophthalmology and Visual Science, USA
| | - Ying Liu
- Department of Ophthalmology and Visual Science, USA
| | - Alina Oltean
- Department of Biomedical Engineering, Washington University, Saint Louis, MO, USA
| | - David C Beebe
- Department of Ophthalmology and Visual Science, USA; Department of Cell Biology and Physiology, Washington University School of Medicine, USA.
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38
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Heermann S, Schütz L, Lemke S, Krieglstein K, Wittbrodt J. Eye morphogenesis driven by epithelial flow into the optic cup facilitated by modulation of bone morphogenetic protein. eLife 2015; 4. [PMID: 25719386 PMCID: PMC4337729 DOI: 10.7554/elife.05216] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Accepted: 01/26/2015] [Indexed: 01/07/2023] Open
Abstract
The hemispheric, bi-layered optic cup forms from an oval optic vesicle during early vertebrate eye development through major morphological transformations. The overall basal surface, facing the developing lens, is increasing, while, at the same time, the space basally occupied by individual cells is decreasing. This cannot be explained by the classical view of eye development. Using zebrafish (Danio rerio) as a model, we show that the lens-averted epithelium functions as a reservoir that contributes to the growing neuroretina through epithelial flow around the distal rims of the optic cup. We propose that this flow couples morphogenesis and retinal determination. Our 4D data indicate that future stem cells flow from their origin in the lens-averted domain of the optic vesicle to their destination in the ciliary marginal zone. BMP-mediated inhibition of the flow results in ectopic neuroretina in the RPE domain. Ultimately the ventral fissure fails to close resulting in coloboma. DOI:http://dx.doi.org/10.7554/eLife.05216.001 The eye is our most important organ for sensing and recognizing our environment. In humans and other vertebrates, the eye forms from an outgrowth of the brain as the embryo develops. This outgrowth is called the optic vesicle and it is rapidly transformed into a cup-shaped structure known as the optic cup. Defects in this process prevent the optic cup from closing completely, which leads to a severe condition called Coloboma—one of the most frequent causes of blindness in children. The optic cup has two distinct layers: the inside layer—known as the neuroretina—contains light sensitive cells and is surrounded by the other layer called the pigmented epithelium. It is thought that the neural retina is made from cells from the side of the optic vesicle that faces the lens, and the pigmented epithelium is formed by cells from the other side of the vesicle. This is a plausible explanation and is well accepted, but it cannot explain how the neuroretina can become five times larger as the cup forms. Heermann et al. addressed this problem by using four-dimensional in vivo microscopy to follow individual cells as the optic cup forms in living zebrafish embryos. The experiments show that the neuroretina is made of cells from both sides of the optic vesicle. Cells from the back of the optic vesicle (furthest away from the lens) join the rest of the cells by moving around the outside rim of the cup. Further experiments found that a signaling molecule called BMP—which is crucial to the normal development of the eye—controls the flow of cells around the developing optic cup. This factor needs to be carefully controlled during the development of the eye; when BMP activity was artificially increased, the flow of cells stopped, resulting in neuroretinal tissue developing in the wrong place (in the outer layer of the optic cup). The experiments also reveal that the stem cells in the retina—which divide to produce new cells throughout the life of the zebrafish—originate from two distinct areas in the optic vesicle. Heermann et al.'s findings challenge the textbook model of eye development by revealing that cells from both sides of the optic vesicle contribute to the neuroretina and that retinal stem cells originate from a specific place in the developing eye. A future challenge will be to understand how the movement of the cells into the neuroretina is coordinated to make a perfectly shaped eye. DOI:http://dx.doi.org/10.7554/eLife.05216.002
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Affiliation(s)
- Stephan Heermann
- Centre for Organismal Studies Heidelberg, Ruprecht Karls Universität, Heidelberg, Germany
| | - Lucas Schütz
- Centre for Organismal Studies Heidelberg, Ruprecht Karls Universität, Heidelberg, Germany
| | - Steffen Lemke
- Centre for Organismal Studies Heidelberg, Ruprecht Karls Universität, Heidelberg, Germany
| | - Kerstin Krieglstein
- Department of Molecular Embryology, Institute of Anatomy and Cell Biology, University Freiburg, Freiburg, Germany
| | - Joachim Wittbrodt
- Centre for Organismal Studies Heidelberg, Ruprecht Karls Universität, Heidelberg, Germany
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39
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Venters SJ, Mikawa T, Hyer J. Early divergence of central and peripheral neural retina precursors during vertebrate eye development. Dev Dyn 2014; 244:266-76. [PMID: 25329498 DOI: 10.1002/dvdy.24218] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Revised: 10/07/2014] [Accepted: 10/12/2014] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND During development of the vertebrate eye, optic tissue is progressively compartmentalized into functionally distinct tissues. From the central to the peripheral optic cup, the original optic neuroepithelial tissue compartmentalizes, forming retina, ciliary body, and iris. The retina can be further sub-divided into peripheral and central compartments, where the central domain is specialized for higher visual acuity, having a higher ratio and density of cone photoreceptors in most species. RESULTS Classically, models depict a segregation of the early optic cup into only two domains, neural and non-neural. Recent studies, however, uncovered discrete precursors for central and peripheral retina in the optic vesicle, indicating that the neural retina cannot be considered as a single unit with homogeneous specification and development. Instead, central and peripheral retina may be subject to distinct developmental pathways that underlie their specialization. CONCLUSIONS This review focuses on lineage relationships in the retina and revisits the historical context for segregation of central and peripheral retina precursors before overt eye morphogenesis.
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Affiliation(s)
- Sara J Venters
- Cardiovascular Research Institute, University of California, San Francisco, California; Department of Neurosurgery, University of California, San Francisco San Francisco, California
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40
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Hosseini HS, Beebe DC, Taber LA. Mechanical effects of the surface ectoderm on optic vesicle morphogenesis in the chick embryo. J Biomech 2014; 47:3837-46. [PMID: 25458577 DOI: 10.1016/j.jbiomech.2014.10.018] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Revised: 10/09/2014] [Accepted: 10/13/2014] [Indexed: 01/14/2023]
Abstract
Precise shaping of the eye is crucial for proper vision. Here, we use experiments on chick embryos along with computational models to examine the mechanical factors involved in the formation of the optic vesicles (OVs), which grow outward from the forebrain of the early embryo. First, mechanical dissections were used to remove the surface ectoderm (SE), a membrane that contacts the outer surfaces of the OVs. Principal components analysis of OV shapes suggests that the SE exerts asymmetric loads that cause the OVs to flatten and shear caudally during the earliest stages of eye development and later to bend in the caudal and dorsal directions. These deformations cause the initially spherical OVs to become pear-shaped. Exposure to the myosin II inhibitor blebbistatin reduced these effects, suggesting that cytoskeletal contraction controls OV shape by regulating tension in the SE. To test the physical plausibility of these interpretations, we developed 2-D finite-element models for frontal and transverse cross-sections of the forebrain, including frictionless contact between the SE and OVs. With geometric data used to specify differential growth in the OVs, these models were used to simulate each experiment (control, SE removed, no contraction). For each case, the predicted shape of the OV agrees reasonably well with experiments. The results of this study indicate that differential growth in the OV and external pressure exerted by the SE are sufficient to cause the global changes in OV shape observed during the earliest stages of eye development.
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Affiliation(s)
- Hadi S Hosseini
- Department of Biomedical Engineering, Washington University, Campus Box 1097, St. Louis, MO 63130, USA; Department of Physics, Washington University, St Louis, MO 63130, USA
| | - David C Beebe
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Larry A Taber
- Department of Biomedical Engineering, Washington University, Campus Box 1097, St. Louis, MO 63130, USA.
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Kwan KM. Coming into focus: the role of extracellular matrix in vertebrate optic cup morphogenesis. Dev Dyn 2014; 243:1242-8. [PMID: 25044784 DOI: 10.1002/dvdy.24162] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Revised: 06/12/2014] [Accepted: 06/25/2014] [Indexed: 02/06/2023] Open
Abstract
The vertebrate eye acquires its basic form during the process of optic cup morphogenesis, during which the optic vesicle emerges from the brain neuroepithelium and, through a series of cell and tissue movements, transforms itself into the multilayered optic cup, containing neural retina (comprised of retinal progenitors), retinal pigmented epithelium, and the lens, which is derived from the overlying ectoderm. While great strides have been made to understand the developmental signals controlling specification, patterning, and differentiation of the optic cup, only in recent years have the cellular and molecular bases of optic cup morphogenesis begun to be unraveled. One critical component of the morphogenetic process is the extracellular matrix: the complex, glycoprotein-rich layer that surrounds the optic vesicle and lens. Though the extracellular matrix has long been visualized by classical histological techniques and postulated to play various roles in optic cup development, its functional role was uncertain. This is now beginning to change, as live imaging techniques, quantitative image analyses, molecular genetics and in vitro models yield new insights into the process of optic cup morphogenesis and the specific influences of particular extracellular matrix components and their associated signaling pathways.
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Affiliation(s)
- Kristen M Kwan
- Department of Human Genetics, University of Utah, Salt Lake City, Utah
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Layer PG, Araki M, Vogel-Höpker A. New concepts for reconstruction of retinal and pigment epithelial tissues. EXPERT REVIEW OF OPHTHALMOLOGY 2014. [DOI: 10.1586/eop.10.42] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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43
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Yip HK. Retinal stem cells and regeneration of vision system. Anat Rec (Hoboken) 2013; 297:137-60. [PMID: 24293400 DOI: 10.1002/ar.22800] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Accepted: 09/13/2013] [Indexed: 12/14/2022]
Abstract
The vertebrate retina is a well-characterized model for studying neurogenesis. Retinal neurons and glia are generated in a conserved order from a pool of mutlipotent progenitor cells. During retinal development, retinal stem/progenitor cells (RPC) change their competency over time under the influence of intrinsic (such as transcriptional factors) and extrinsic factors (such as growth factors). In this review, we summarize the roles of these factors, together with the understanding of the signaling pathways that regulate eye development. The information about the interactions between intrinsic and extrinsic factors for retinal cell fate specification is useful to regenerate specific retinal neurons from RPCs. Recent studies have identified RPCs in the retina, which may have important implications in health and disease. Despite the recent advances in stem cell biology, our understanding of many aspects of RPCs in the eye remains limited. PRCs are present in the developing eye of all vertebrates and remain active in lower vertebrates throughout life. In mammals, however, PRCs are quiescent and exhibit very little activity and thus have low capacity for retinal regeneration. A number of different cellular sources of RPCs have been identified in the vertebrate retina. These include PRCs at the retinal margin, pigmented cells in the ciliary body, iris, and retinal pigment epithelium, and Müller cells within the retina. Because PRCs can be isolated and expanded from immature and mature eyes, it is possible now to study these cells in culture and after transplantation in the degenerated retinal tissue. We also examine current knowledge of intrinsic RPCs, and human embryonic stems and induced pluripotent stem cells as potential sources for cell transplant therapy to regenerate the diseased retina.
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Affiliation(s)
- Henry K Yip
- Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Adminstrative Region, People's Republic of China; Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Adminstrative Region, People's Republic of China; State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Pokfulam, Hong Kong Special Adminstrative Region, People's Republic of China
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Steinfeld J, Steinfeld I, Coronato N, Hampel ML, Layer PG, Araki M, Vogel-Höpker A. RPE specification in the chick is mediated by surface ectoderm-derived BMP and Wnt signalling. Development 2013; 140:4959-69. [PMID: 24227655 DOI: 10.1242/dev.096990] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The retinal pigment epithelium (RPE) is indispensable for vertebrate eye development and vision. In the classical model of optic vesicle patterning, the surface ectoderm produces fibroblast growth factors (FGFs) that specify the neural retina (NR) distally, whereas TGFβ family members released from the proximal mesenchyme are involved in RPE specification. However, we previously proposed that bone morphogenetic proteins (BMPs) released from the surface ectoderm are essential for RPE specification in chick. We now show that the BMP- and Wnt-expressing surface ectoderm is required for RPE specification. We reveal that Wnt signalling from the overlying surface ectoderm is involved in restricting BMP-mediated RPE specification to the dorsal optic vesicle. Wnt2b is expressed in the dorsal surface ectoderm and subsequently in dorsal optic vesicle cells. Activation of Wnt signalling by implanting Wnt3a-soaked beads or inhibiting GSK3β at optic vesicle stages inhibits NR development and converts the entire optic vesicle into RPE. Surface ectoderm removal at early optic vesicle stages or inhibition of Wnt, but not Wnt/β-catenin, signalling prevents pigmentation and downregulates the RPE regulatory gene Mitf. Activation of BMP or Wnt signalling can replace the surface ectoderm to rescue MITF expression and optic cup formation. We provide evidence that BMPs and Wnts cooperate via a GSK3β-dependent but β-catenin-independent pathway at the level of pSmad to ensure RPE specification in dorsal optic vesicle cells. We propose a new dorsoventral model of optic vesicle patterning, whereby initially surface ectoderm-derived Wnt signalling directs dorsal optic vesicle cells to develop into RPE through a stabilising effect of BMP signalling.
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Affiliation(s)
- Jörg Steinfeld
- Fachgebiet Entwicklungsbiologie und Neurogenetik, Technische Universität Darmstadt, Schnittspahnstrasse 13, D-64287 Darmstadt, Germany
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Fuhrmann S, Zou C, Levine EM. Retinal pigment epithelium development, plasticity, and tissue homeostasis. Exp Eye Res 2013; 123:141-50. [PMID: 24060344 DOI: 10.1016/j.exer.2013.09.003] [Citation(s) in RCA: 185] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Revised: 09/05/2013] [Accepted: 09/07/2013] [Indexed: 12/13/2022]
Abstract
The retinal pigment epithelium (RPE) is a simple epithelium interposed between the neural retina and the choroid. Although only 1 cell-layer in thickness, the RPE is a virtual workhorse, acting in several capacities that are essential for visual function and preserving the structural and physiological integrities of neighboring tissues. Defects in RPE function, whether through chronic dysfunction or age-related decline, are associated with retinal degenerative diseases including age-related macular degeneration. As such, investigations are focused on developing techniques to replace RPE through stem cell-based methods, motivated primarily because of the seemingly limited regeneration or self-repair properties of mature RPE. Despite this, RPE cells have an unusual capacity to transdifferentiate into various cell types, with the particular fate choices being highly context-dependent. In this review, we describe recent findings elucidating the mechanisms and steps of RPE development and propose a developmental framework for understanding the apparent contradiction in the capacity for low self-repair versus high transdifferentiation.
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Affiliation(s)
- Sabine Fuhrmann
- Department of Ophthalmology & Visual Sciences, John A. Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT 84132, USA.
| | - ChangJiang Zou
- Department of Ophthalmology & Visual Sciences, John A. Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT 84132, USA.
| | - Edward M Levine
- Department of Ophthalmology & Visual Sciences, John A. Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT 84132, USA.
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Collomb E, Yang Y, Foriel S, Cadau S, Pearton DJ, Dhouailly D. The corneal epithelium and lens develop independently from a common pool of precursors. Dev Dyn 2013; 242:401-13. [PMID: 23335276 DOI: 10.1002/dvdy.23925] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2012] [Revised: 11/23/2012] [Accepted: 12/24/2012] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND The corneal epithelium (CE) overlays a stroma, which is derived from neural crest cells, and appears to be committed during chick development, but appears still labile in adult rabbit. Its specification was hitherto regarded as resolved and dependent upon the lens, although without experimental support. Here, we challenged CE fate by changing its environment at different stages. RESULTS Recombination with a dermis showed that CE commitment is linked to stroma formation, which results in Pax6 stabilization in both species. Surgical ablation shows that CE specification has already taken place when the lens placode invaginates, while removal of the early lens placode led to lens renewal. To block lens formation, bone morphogenetic protein (BMP) signaling, one of its last inducing factors, was inhibited by over-expression of Gremlin in the ocular ectoderm. This resulted in lens-less embryos which formed a corneal epithelium if they survived 2 weeks. CONCLUSION The corneal epithelium and lens share a common pool of precursors. The adoption of the CE fate might be dependent on the loss of a lens placode favoring environment. The corneal fate is definitively stabilized by the migration of Gremlin-expressing neural crest cells in the lens peripheral ectoderm.
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Affiliation(s)
- Elodie Collomb
- FRE CNRS 3405, AGIM, Université Joseph Fourier Grenoble, Site Santé, France
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Sasai Y, Eiraku M, Suga H. In vitro organogenesis in three dimensions: self-organising stem cells. Development 2013; 139:4111-21. [PMID: 23093423 DOI: 10.1242/dev.079590] [Citation(s) in RCA: 134] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Organ formation during embryogenesis is a complex process that involves various local cell-cell interactions at the molecular and mechanical levels. Despite this complexity, organogenesis can be modelled in vitro. In this article, we focus on two recent examples in which embryonic stem cells can self-organise into three-dimensional structures - the optic cup and the pituitary epithelium; and one case of self-organising adult stem cells - the gut epithelium. We summarise how these approaches have revealed intrinsic programs that drive locally autonomous modes of organogenesis and homeostasis. We also attempt to interpret the results of previous in vivo studies of retinal development in light of the self-organising nature of the retina.
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Affiliation(s)
- Yoshiki Sasai
- Neurogenesis and Organogenesis Group, RIKEN Center for Developmental Biology, Kobe, Japan.
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Abstract
Organogenesis is regulated by a complex network of intrinsic cues, diffusible signals and cell/cell or cell/matrix interactions that drive the cells of a prospective organ to differentiate and collectively organize in three dimensions. Generating organs in vitro from embryonic stem (ES) cells may provide a simplified system to decipher how these processes are orchestrated in time and space within particular and between neighboring tissues. Recently, this field of stem cell research has also gained considerable interest for its potential applications in regenerative medicine. Among human pathologies for which stem cell-based therapy is foreseen as a promising therapeutic strategy are many retinal degenerative diseases, like retinitis pigmentosa and age-related macular degeneration. Over the last decade, progress has been made in producing ES-derived retinal cells in vitro, but engineering entire synthetic retinas was considered beyond reach. Recently however, major breakthroughs have been achieved with pioneer works describing the extraordinary self-organization of murine and human ES cells into a three dimensional structure highly resembling a retina. ES-derived retinal cells indeed assemble to form a cohesive neuroepithelial sheet that is endowed with the intrinsic capacity to recapitulate, outside an embryonic environment, the main steps of retinal morphogenesis as observed in vivo. This represents a tremendous advance that should help resolving fundamental questions related to retinogenesis. Here, we will discuss these studies, and the potential applications of such stem cell-based systems for regenerative medicine.
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Affiliation(s)
- Gabriele Colozza
- Gabriele Colozza, Morgane Locker, Muriel Perron, Laboratory of Neurobiology and Development, UPR CNRS 3294, University Paris-Sud, 91405 ORSAY Cedex, France
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Kwan KM, Otsuna H, Kidokoro H, Carney KR, Saijoh Y, Chien CB. A complex choreography of cell movements shapes the vertebrate eye. Development 2012; 139:359-72. [PMID: 22186726 PMCID: PMC3243097 DOI: 10.1242/dev.071407] [Citation(s) in RCA: 96] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Optic cup morphogenesis (OCM) generates the basic structure of the vertebrate eye. Although it is commonly depicted as a series of epithelial sheet folding events, this does not represent an empirically supported model. Here, we combine four-dimensional imaging with custom cell tracking software and photoactivatable fluorophore labeling to determine the cellular dynamics underlying OCM in zebrafish. Although cell division contributes to growth, we find it dispensable for eye formation. OCM depends instead on a complex set of cell movements coordinated between the prospective neural retina, retinal pigmented epithelium (RPE) and lens. Optic vesicle evagination persists for longer than expected; cells move in a pinwheel pattern during optic vesicle elongation and retinal precursors involute around the rim of the invaginating optic cup. We identify unanticipated movements, particularly of central and peripheral retina, RPE and lens. From cell tracking data, we generate retina, RPE and lens subdomain fate maps, which reveal novel adjacencies that might determine corresponding developmental signaling events. Finally, we find that similar movements also occur during chick eye morphogenesis, suggesting that the underlying choreography is conserved among vertebrates.
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Affiliation(s)
- Kristen M Kwan
- Department of Neurobiology and Anatomy, Salt Lake City, UT 84132, USA.
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Shah SP, Taylor AE, Sowden JC, Ragge N, Russell-Eggitt I, Rahi JS, Gilbert CE. Anophthalmos, microphthalmos, and Coloboma in the United kingdom: clinical features, results of investigations, and early management. Ophthalmology 2012; 119:362-8. [PMID: 22054996 DOI: 10.1016/j.ophtha.2011.07.039] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2011] [Revised: 07/11/2011] [Accepted: 07/21/2011] [Indexed: 10/15/2022] Open
Abstract
PURPOSE To describe the clinical features of children with anophthalmos, microphthalmos, and typical coloboma (AMC). DESIGN Descriptive, observational, cross-sectional study of the United Kingdom. PARTICIPANTS A total of 135 children with AMC newly diagnosed over an 18-month period beginning in October 2006. METHODS Cases were identified using active surveillance through an established ophthalmic surveillance system. Eligible cases were followed up 6 months after first notification. MAIN OUTCOME MEASURES Phenotypic characteristics, both ocular and systemic, clinical investigations, causes, and interventions. RESULTS A total of 210 eyes (of 135 children) were affected by AMC, of which 153 had isolated coloboma or coloboma with microphthalmos. The most common colobomatous anomaly was a chorioretinal defect present in 109 eyes (71.2%). Some 44% of children were bilaterally visually impaired. Systemic abnormalities were present in 59.7% of children, with craniofacial anomalies being the most common. Children with bilateral disease had a 2.7 times higher odds (95% confidence interval, 1.3-5.5, P = 0.006) of having systemic involvement than unilaterally affected children. Neurologic imaging was the most frequent investigation (58.5%) performed. Less than one third (30.3%) of the children with microphthalmos had ocular axial lengths measured. Eight children had confirmed genetic mutations. Approximately half (49.2%) of the children required ocular intervention. CONCLUSIONS Colobomatous defects were the most common phenotype within this spectrum of anomalies in the United Kingdom. The high frequency of posterior segment colobomatous involvement means that a dilated fundal examination should be made in all cases. The significant visual and systemic morbidity in affected children underlines the importance of a multidisciplinary approach to management.
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Affiliation(s)
- Shaheen P Shah
- International Centre for Eye Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.
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