Talk:Vision - Retina Development

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Cite this page: Hill, M.A. (2021, August 4) Embryology Vision - Retina Development. Retrieved from


Analysis of expression of transcription factors in early human retina

Int J Dev Neurosci. 2017 Apr 3. pii: S0736-5748(16)30113-7. doi: 10.1016/j.ijdevneu.2017.01.015. [Epub ahead of print]

Chen J1, Ma L1, Wang S1, Wang X1, Sun Y1, Gao L1, Li J2, Zhou G3. Author information Abstract The retina originates in the central nervous system. Due to its accessibility and simplicity, the retina has become an invaluable model for studying the basic mechanisms involved in development. To date, considerable knowledge regarding the interactions among genes that coordinate retinal development has been gained from extensive research in model animals. However, our understanding of retinal development in humans remains undeveloped. Here, we analyze the expression of transcription factors that are involved in the early development of the retina in human embryos at 6-12 weeks post-conception. Our work demonstrates that early developing neural retinas can be divided into two layers, the outer and inner neuroblast layers. Eye-field transcription factors and those related to the early development of the retina have distinct expression patterns in the two layers. Cell-type-specific transcription factors emerge at 8 weeks. These data provide clear and systemic structures for early retinal development in human. Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved. KEYWORDS: Human embryo; Retina development; Transcription factors PMID 28377129 DOI: 10.1016/j.ijdevneu.2017.01.015


Development of Retinal Layers in Prenatal Human Retina

Am J Ophthalmol. 2015 Sep 24. pii: S0002-9394(15)00593-0. doi: 10.1016/j.ajo.2015.09.023. [Epub ahead of print]

Hendrickson A.


PURPOSE: To determine the developmental sequence of retinal layers to provide information on where in utero pathological events might affect retinal development. DESIGN: Qualitative and quantitative descriptive research. METHODS: A histology collection of human eyes from fetal week (Fwk) 8 to postnatal (P) 10 weeks was analyzed. The length of the nasal and temporal retina was measured along the horizontal meridian in 20 eyes. The location of the inner plexiform layer (IPL) and outer plexiform layer (OPL) was identified at each age, and its length measured. RESULTS: The human eye retinal length increased from 5.19 mm at Fwk 8 to 20.92 mm at midgestation to 32.88 mm just after birth. The IPL appeared in the presumptive fovea at Fwk 8, reached the eccentricity of the optic nerve by Fwk 12 and was present to both nasal and temporal peripheral edges by Fwk 18-21. By contrast, the OPL developed slowly. A short OPL was first present in the Fwk 11 fovea and did not reach the eccentricity of the optic nerve until midgestation. The OPL reached the retinal edges by Fwk 30. Laminar development of both IPL and OPL occurred before vascular formation CONCLUSIONS: In human fetal retina, the IPL reached the far peripheral edge of the retina by midgestation and the OPL by late gestation. Only very early in utero events could affect IPL lamination in central retina, but events occurring after Fwk 20 in peripheral retina would overlap OPL laminar development in outer retina. Copyright © 2015 Elsevier Inc. All rights reserved.

PMID 26410132


A complex choreography of cell movements shapes the vertebrate eye

Development. 2012 Jan;139(2):359-72.

Kwan KM, Otsuna H, Kidokoro H, Carney KR, Saijoh Y, Chien CB.

Source Department of Neurobiology and Anatomy, Salt Lake City, UT 84132, USA.


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.

PMID 22186726

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License, which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms.

Roles of homeobox genes in retinal ganglion cell differentiation and axonal guidance

Adv Exp Med Biol. 2012;723:685-91.

Zhang Q, Eisenstat DD. Source Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, MB, Canada, R3E 0V9.


In this review, we have described four major families of homeobox genes which play important roles in RGC differentiation as well as axonal pathfinding. The mechanism underlying how these HD TFs affect axonal pathfinding is not entirely known. One possibility is that the downstream targets directly regulated by these HD TF are responsible for axonal guidance. Examples of this are the repression of EphB1 by Isl2, and Vax1/Vax2 regulation of EphB2/EphB3 expression. The roles of Dlx homeobox genes in RGC axonal guidance have not yet been reported. However, in the mouse telencephalon, Dlx1 and Dlx2 promote the tangential migration of GABAergic interneurons by repressing axonal growth (Cobos et al. 2007) and inhibiting Neuropilin-2 expression (Le et al. 2007). It is possible that the genetic program defining RGC identity also encodes a unique "sensory" network for their axons, determining how and where RGC axons respond to guidance cues en route to CNS targets.

PMID 22183394


Evolutionary relationships and diversification of barhl genes within retinal cell lineages

BMC Evol Biol. 2011 Nov 21;11:340.

Schuhmacher LN, Albadri S, Ramialison M, Poggi L. Source Centre for Organismal Studies, University of Heidelberg, Heidelberg 69120, Germany.


BACKGROUND: Basic helix-loop-helix and homeodomain transcription factors have been shown to specify all different neuronal cell subtypes composing the vertebrate retina. The appearance of gene paralogs of such retina-specific transcription factors in lower vertebrates, with differently evolved function and/or conserved non-coding elements, might provide an important source for the generation of neuronal diversity within the vertebrate retinal architecture. In line with this hypothesis, we investigated the evolution of the homeobox Barhl family of transcription factors, barhl1 and barhl2, in the teleost and tetrapod lineages. In tetrapod barhl2, but not barhl1, is expressed in the retina and is important for amacrine cell specification. Zebrafish has three barhl paralogs: barhl1.1, barhl1.2 and barhl2, but their precise spatio-temporal retinal expression, as well as their function is yet unknown. RESULTS: Here we performed a meticulous expression pattern comparison of all known barhl fish paralogs and described a novel barhl paralog in medaka. Our detailed analysis of zebrafish barhl gene expression in wild type and mutant retinas revealed that only barhl1.2 and barhl2 are present in the retina. We also showed that these two paralogs are expressed in distinct neuronal lineages and are differently regulated by Atoh7, a key retinal-specific transcription factor. Finally, we found that the two retained medaka fish barhl paralogs, barhl1 and barhl2, are both expressed in the retina, in a pattern reminiscent of zebrafish barhl1.2 and barhl2 respectively. By performing phylogenetic and synteny analysis, we provide evidence that barhl retinal expression domain is an ancestral feature, probably lost in tetrapods due to functional redundancy. CONCLUSIONS: Functional differences among retained paralogs of key retina-specific transcription factors between teleosts and tetrapods might provide important clues for understanding their potential impact on the generation of retinal neuronal diversity. Intriguingly, within teleosts, retention of zebrafish barhl1.2 and its medaka ortholog barhl1 appears to correlate with the acquisition of distinct signalling mechanisms by the two genes within distinct retinal cell lineages. Our findings provide a starting point for the study of barhl gene evolution in relation to the generation of cell diversity in the vertebrate retina.

PMID 22103894

The cell adhesion-associated protein Git2 regulates morphogenetic movements during zebrafish embryonic development

Dev Biol. 2011 Jan 15;349(2):225-37. Epub 2010 Oct 26.

Yu JA, Foley FC, Amack JD, Turner CE. Source Department of Cell and Developmental Biology, State University of New York, Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.


Signaling through cell adhesion complexes plays a critical role in coordinating cytoskeletal remodeling necessary for efficient cell migration. During embryonic development, normal morphogenesis depends on a series of concerted cell movements; but the roles of cell adhesion signaling during these movements are poorly understood. The transparent zebrafish embryo provides an excellent system to study cell migration during development. Here, we have identified zebrafish git2a and git2b, two new members of the GIT family of genes that encode ArfGAP proteins associated with cell adhesions. Loss-of-function studies revealed an essential role for Git2a in zebrafish cell movements during gastrulation. Time-lapse microscopy analysis demonstrated that antisense depletion of Git2a greatly reduced or arrested cell migration towards the vegetal pole of the embryo. These defects were rescued by expression of chicken GIT2, indicating a specific and conserved role for Git2 in controlling embryonic cell movements. Git2a knockdown embryos showed defects in cell morphology that were associated with reduced cell contractility. We show that Git2a is required for phosphorylation of myosin light chain (MLC), which regulates myosin II-mediated cell contractility. Consistent with this, embryos treated with Blebbistatin-a small molecule inhibitor for myosin II activity-exhibited cell movement defects similar to git2a knockdown embryos. These observations provide in vivo evidence of a physiologic role for Git2a in regulating cell morphogenesis and directed cell migration via myosin II activation during zebrafish embryonic development. Copyright © 2010 Elsevier Inc. All rights reserved.

PMID 21034731


Role of afferents in the differentiation of bipolar cells in the mouse retina

J Neurosci. 2010 Feb 3;30(5):1677-85.

Keeley PW, Reese BE. Department of Molecular, Cellular, and Developmental Biology, and Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, California 93106, USA.

Abstract To establish dendritic arbors that integrate properly into a neural circuit, neurons must rely on cues from the local environment. The neurons presynaptic to these arbors, the afferents, are one potential source of these cues, but the particular dendritic features they regulate remain unclear. Retinal bipolar cells can be classified by the type of photoreceptor, cone or rod, forming synaptic contacts with their dendrites, suggesting a potential role of these afferents in shaping the bipolar cell dendritic arbor. In the present investigation, the role of photoreceptors in directing the differentiation of bipolar cells has been studied using two genetically modified "coneless" and "conefull" mice. Single cone (Type 7/CB4a) and rod bipolar cells were labeled with DiI to reveal the entire dendritic arbor and subsequently analyzed for several morphological features. For both cone and rod bipolar cells, the dendritic field area, number of dendritic terminals, and stratification of terminals in the outer plexiform layer were comparable among coneless, conefull, and wild-type retinas, and the overall morphological appearance of each type of cell was essentially conserved, indicating an independence from afferent specification. The presence of normal afferents was, however, found to be critical for the proper spatial distribution of dendritic terminals, exhibiting a clustered distribution for the cone bipolar cells and a dispersed distribution for the rod bipolar cells. These results demonstrate a selectivity in the afferent dependency of bipolar cell differentiation, their basic morphogenetic plan commanded cell intrinsically, and their fine terminal connectivity directed by the afferents themselves.

PMID 20130177

The expression of Wnt2b in the optic cup lip requires a border between the pigmented and non pigmented epithelium

Mol Vis. 2010 Dec 14;16:2701-17.

Kitamoto J, Hyer J. Source Department of Ophthalmology and Neurosurgery, University of California, San Francisco, CA 94143, USA.


PURPOSE: Wnt2b is normally expressed at the optic cup lip and is implicated in ciliary body induction. The lens has often been considered an organizer for the anterior eye, but recent studies demonstrate that the anterior cell fates are correctly specified in the absence of the lens. This study uses Wnt2b as a marker to reveal the mechanism behind the specification of the anterior domain of the optic cup. METHODS: Developing chick embryos were used as a model system. Eyes were microsurgically manipulated to assess the role of the lens in the development of the anterior optic cup. Eyes were molecularly manipulated, using fibroblast growth factor expressing replication-incompetent retrovirus, introduced into the retinal pigmented epithelium (RPE) domain. Ectopic fibroblast growth factor transformed the RPE into nonpigmented epithelium (NPE; ciliary body). As the virus does not spread, discrete borders between RPE and NPE were experimentally created. Wnt2b expression was assessed after surgical and molecular manipulation. RESULTS: Contrary to expectations, we found that the lens is not able to induce Wnt2b expression in optic cup tissue: When the optic cup lip is experimentally misspecified such that it no longer contains the juxtaposition of pigmented and nonpigmented tissue, Wnt2b is not expressed. In addition, if the prelens ectoderm is removed from the optic vesicle before morphogenesis, the resulting lensless optic cup expresses Wnt2b even though it was not in contact with lens tissue. We also show that ectopic lenses do not induce Wnt2b in optic cup tissue. The ciliary body/anterior eye domain is specified at the border of RPE and the NPE of the ciliary body. During development, this border is normally found at the optic cup lip. We can manipulate tissue specification using retroviral-mediated gene transfer, and create ectopic borders between nonpigmented and pigmented tissue. At such borders, Wnt2b is ectopically expressed in the absence of lens contact. Finally, we describe a role for the lens in maintenance of Wnt2b expression and demonstrate support for this in two ways: First, we show that if the lens is removed from the formed optic cup, endogenous Wnt2b expression is specifically lost from the optic cup lip; and second, we show that while ectopic Wnt2b expression is initially found in the majority of ectopic borders, as eye development proceeds ectopic expression is maintained only in those borders that are close to the lens. CONCLUSIONS: Taken together, the results provide support for a model in which the anterior optic cup domain, as described in part by Wnt2b expression, is specified through the elaboration of a border within the optic neuroepithelium rather than through interactions with the surrounding environment.

PMID 21179237


Dynamic coupling of pattern formation and morphogenesis in the developing vertebrate retina

PLoS Biol. 2009 Oct;7(10):e1000214. Epub 2009 Oct 13.

Picker A, Cavodeassi F, Machate A, Bernauer S, Hans S, Abe G, Kawakami K, Wilson SW, Brand M. Center of Regenerative Therapies Dresden, Biotechnology Center, Dresden University of Technology, Dresden, Germany.

Abstract During embryonic development, pattern formation must be tightly synchronized with tissue morphogenesis to coordinate the establishment of the spatial identities of cells with their movements. In the vertebrate retina, patterning along the dorsal-ventral and nasal-temporal (anterior-posterior) axes is required for correct spatial representation in the retinotectal map. However, it is unknown how specification of axial cell positions in the retina occurs during the complex process of early eye morphogenesis. Studying zebrafish embryos, we show that morphogenetic tissue rearrangements during eye evagination result in progenitor cells in the nasal half of the retina primordium being brought into proximity to the sources of three fibroblast growth factors, Fgf8/3/24, outside the eye. Triple-mutant analysis shows that this combined Fgf signal fully controls nasal retina identity by regulating the nasal transcription factor Foxg1. Surprisingly, nasal-temporal axis specification occurs very early along the dorsal-ventral axis of the evaginating eye. By in vivo imaging GFP-tagged retinal progenitor cells, we find that subsequent eye morphogenesis requires gradual tissue compaction in the nasal half and directed cell movements into the temporal half of the retina. Balancing these processes drives the progressive alignment of the nasal-temporal retina axis with the anterior-posterior body axis and is controlled by a feed-forward effect of Fgf signaling on Foxg1-mediated cell cohesion. Thus, the mechanistic coupling and dynamic synchronization of tissue patterning with morphogenetic cell behavior through Fgf signaling leads to the graded allocation of cell positional identity in the eye, underlying retinotectal map formation.

PMID 19823566


Iris development in vertebrates; genetic and molecular considerations

Brain Res. 2008 Feb 4;1192:17-28. Epub 2007 Mar 20.

Davis-Silberman N, Ashery-Padan R. Sackler Faculty of Medicine, Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Ramat Aviv 69978, Tel Aviv, Israel.

Abstract The iris plays a key role in visual function. It regulates the amount of light entering the eye and falling on the retina and also operates in focal adjustment of closer objects. The iris is involved in circulation of the aqueous humor and hence functions in regulation of intraocular pressure. Intriguingly, iris pigmented cells possess the ability to transdifferentiate into different ocular cell types of retinal pigmented epithelium, photoreceptors and lens cells. Thus, the iris is considered a potential source for cell-replacement therapies. During embryogenesis, the iris arises from both the optic cup and the periocular mesenchyme. Its interesting mode of development includes specification of the peripheral optic cup to a non-neuronal fate, migration of cells from the surrounding periocular mesenchyme and an atypical formation of smooth muscles from the neuroectoderm. This manner of development raises some interesting general topics concerning the early patterning of the neuroectoderm, the specification and differentiation of diverse cell types and the interactions between intrinsic and extrinsic factors in the process of organogenesis. In this review, we discuss iris anatomy and development, describe major pathologies of the iris and their molecular etiology and finally summarize the recent findings on genes and signaling pathways that are involved in iris development.

PMID 17466284