The role of bone morphogenetic proteins in the differentiation of the ventral optic cup

Development ◽  
2002 ◽  
Vol 129 (13) ◽  
pp. 3161-3171 ◽  
Author(s):  
Ruben Adler ◽  
Teri L. Belecky-Adams
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Ectopic Expression ◽  
Neural Retina ◽  
Optic Disk ◽  
Loss Of Function ◽  
In Ovo ◽  
Optic Stalk ◽  
Optic Cup

The ventral region of the chick embryo optic cup undergoes a complex process of differentiation leading to the formation of four different structures: the neural retina, the retinal pigment epithelium (RPE), the optic disk/optic stalk, and the pecten oculi. Signaling molecules such as retinoic acid and sonic hedgehog have been implicated in the regulation of these phenomena. We have now investigated whether the bone morphogenetic proteins (BMPs) also regulate ventral optic cup development. Loss-of-function experiments were carried out in chick embryos in ovo, by intraocular overexpression of noggin, a protein that binds several BMPs and prevents their interactions with their cognate cell surface receptors. At optic vesicle stages of development, this treatment resulted in microphthalmia with concomitant disruption of the developing neural retina, RPE and lens. At optic cup stages, however, noggin overexpression caused colobomas, pecten agenesis, replacement of the ventral RPE by neuroepithelium-like tissue, and ectopic expression of optic stalk markers in the region of the ventral retina and RPE. This was frequently accompanied by abnormal growth of ganglion cell axons, which failed to enter the optic nerve. The data suggest that endogenous BMPs have significant effects on the development of ventral optic cup structures.

Patterning the Vertebrate Retina with Morphogenetic Signaling Pathways

2019 ◽  
Vol 26 (2) ◽  
pp. 185-196 ◽  
Author(s):  
Marcos J. Cardozo ◽  
María Almuedo-Castillo ◽  
Paola Bovolenta
Keyword(s):  
Signaling Pathways ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Subsequent Development ◽  
Neural Retina ◽  
Bmp Signaling ◽  
Vertebrate Species ◽  
Optic Stalk ◽  
Optic Cup ◽  
Vertebrate Eye

The primordium of the vertebrate eye is composed of a pseudostratified and apparently homogeneous neuroepithelium, which folds inward to generate a bilayered optic cup. During these early morphogenetic events, the optic vesicle is patterned along three different axes—proximo-distal, dorso-ventral, and naso-temporal—and three major domains: the neural retina, the retinal pigment epithelium (RPE), and the optic stalk. These fundamental steps that enable the subsequent development of a functional eye, entail the precise coordination among genetic programs. These programs are driven by the interplay of signaling pathways and transcription factors, which progressively dictate how each tissue should evolve. Here, we discuss the contribution of the Hh, Wnt, FGF, and BMP signaling pathways to the early patterning of the retina. Comparative studies in different vertebrate species have shown that their morphogenetic activity is repetitively used to orchestrate the progressive specification of the eye with evolutionary conserved mechanisms that have been adapted to match the specific need of a given species.

scholarly journals Spatial specification of mammalian eye territories by reciprocal transcriptional repression of Pax2 and Pax6

Development ◽  
2000 ◽  
Vol 127 (20) ◽  
pp. 4325-4334 ◽  
Author(s):  
M. Schwarz ◽  
F. Cecconi ◽  
G. Bernier ◽  
N. Andrejewski ◽  
B. Kammandel ◽  
...  
Keyword(s):  
Visual System ◽  
Transcriptional Repression ◽  
Ectopic Expression ◽  
Pax6 Gene ◽  
Loss Of Function ◽  
Pax6 Expression ◽  
Expression Domain ◽  
Enhancer Activity ◽  
Optic Stalk ◽  
Optic Cup

We have studied the molecular basis of the Pax2 and Pax6 function in the establishment of visual system territories. Loss-of-function mutants have revealed crucial roles for Pax2 in the generation of the optic stalk and for Pax6 in the development of the optic cup. Ectopic expression of Pax6 in the optic stalk under control of Pax2 promoter elements resulted in a shift of the optic cup/optic stalk boundary indicated by the presence of retinal pigmented cells on the optic stalk. By studying mouse embryos at early developmental stages we detected an expansion of Pax2 expression domain in the Pax6(−/−) mutant and of Pax6 expression domain in the Pax2(−/−) embryo. These results suggest that the position of the optic cup/optic stalk boundary depends on Pax2 and Pax6 expression, hinting at a possible molecular interaction. Using gel shift experiments, we confirmed the presence of Pax2- and Pax6-binding sites on the retina enhancer of the Pax6 gene and on the Pax2 upstream control region, respectively. Co-transfection experiments revealed a reciprocal inhibition of Pax2 promoter/enhancer activity by Pax6 protein and vice versa. Based on our findings, we propose a model for Pax gene regulation that establishes the proper spatial regionalization of the mammalian visual system.

Patterning the optic neuroepithelium by FGF signaling and Ras activation

Development ◽  
2001 ◽  
Vol 128 (24) ◽  
pp. 5051-5060 ◽  
Author(s):  
Shulei Zhao ◽  
Fang-Cheng Hung ◽  
Jennifer S. Colvin ◽  
Andrew White ◽  
Weilie Dai ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Neural Differentiation ◽  
Molecular Mechanisms ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Ectopic Expression ◽  
Neural Retina ◽  
Proximal Region ◽  
Optic Vesicle ◽  
Neural Tissues

During vertebrate embryogenesis, the neuroectoderm differentiates into neural tissues and also into non-neural tissues such as the choroid plexus in the brain and the retinal pigment epithelium in the eye. The molecular mechanisms that pattern neural and non-neural tissues within the neuroectoderm remain unknown. We report that FGF9 is normally expressed in the distal region of the optic vesicle that is destined to become the neural retina, suggesting a role in neural patterning in the optic neuroepithelium. Ectopic expression of FGF9 in the proximal region of the optic vesicle extends neural differentiation into the presumptive retinal pigment epithelium, resulting in a duplicate neural retina in transgenic mice. Ectopic expression of constitutively active Ras is also sufficient to convert the retinal pigment epithelium to neural retina, suggesting that Ras-mediated signaling may be involved in neural differentiation in the immature optic vesicle. The original and the duplicate neural retinae differentiate and laminate with mirror-image polarity in the absence of an RPE, suggesting that the program of neuronal differentiation in the retina is autonomously regulated. In mouse embryos lacking FGF9, the retinal pigment epithelium extends into the presumptive neural retina, indicating a role of FGF9 in defining the boundary of the neural retina.

scholarly journals Stretching of the retinal pigment epithelium contributes to zebrafish optic cup morphogenesis

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Tania Moreno-Mármol ◽  
Mario Ledesma-Terrón ◽  
Noemi Tabanera ◽  
Maria Jesús Martin-Bermejo ◽  
Marcos J Cardozo ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Neural Retina ◽  
Efficient Solutions ◽  
Mechanical Forces ◽  
Rpe Cells ◽  
Virtual Absence ◽  
Optic Cup ◽  
Vertebrate Eye

The vertebrate eye-primordium consists of a pseudostratified neuroepithelium, the optic vesicle (OV), in which cells acquire neural retina or retinal pigment epithelium (RPE) fates. As these fates arise, the OV assumes a cup-shape, influenced by mechanical forces generated within the neural retina. Whether the RPE passively adapts to retinal changes or actively contributes to OV morphogenesis remains unexplored. We generated a zebrafish Tg(E1-bhlhe40:GFP) line to track RPE morphogenesis and interrogate its participation in OV folding. We show that, in virtual absence of proliferation, RPE cells stretch and flatten, thereby matching the retinal curvature and promoting OV folding. Localized interference with the RPE cytoskeleton disrupts tissue stretching and OV folding. Thus, extreme RPE flattening and accelerated differentiation are efficient solutions adopted by fast-developing species to enable timely optic cup formation. This mechanism differs in amniotes, in which proliferation drives RPE expansion with a much-reduced need of cell flattening.

scholarly journals Stretching of the retinal pigment epithelium contributes to zebrafish optic cup morphogenesis

2020 ◽  
Author(s):  
Tania Moreno-Mármol ◽  
Mario Ledesma-Terrón ◽  
Noemí Tabanera ◽  
María Jesús Martin-Bermejo ◽  
Marcos J Cardozo ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Neural Retina ◽  
Efficient Solutions ◽  
Mechanical Forces ◽  
Rpe Cells ◽  
Virtual Absence ◽  
Optic Cup ◽  
Vertebrate Eye

AbstractThe vertebrate eye primordium consists of a pseudostratified neuroepithelium, the optic vesicle (OV), in which cells acquire neural retina or retinal pigment epithelium (RPE) fates. As these fates arise, the OV assumes a cup-shape, influenced by mechanical forces generated within the neural retina. Whether the RPE passively adapts to retinal changes or actively contributes to OV morphogenesis remains unexplored. Here, we generated a zebrafish Tg(E1-bhlhe40:GFP) line to track RPE morphogenesis and interrogate its participation in OV folding. We show that, in virtual absence of proliferation, RPE cells stretch into a squamous configuration, thereby matching the curvature of the underlying retina. Forced proliferation and localized interference with the RPE cytoskeleton disrupt its stretching and OV folding. Thus, extreme RPE flattening and accelerated differentiation are efficient solutions adopted by fast-developing species to enable timely optic cup formation. This mechanism differs in amniotes, in which proliferation largely drives RPE expansion with a much-reduced need of cell flattening.

Midline signalling is required for Pax gene regulation and patterning of the eyes

Development ◽  
1995 ◽  
Vol 121 (10) ◽  
pp. 3267-3278 ◽  
Author(s):  
R. Macdonald ◽  
K.A. Barth ◽  
Q. Xu ◽  
N. Holder ◽  
I. Mikkola ◽  
...  
Keyword(s):  
Developmental Stages ◽  
Pigment Epithelium ◽  
Neural Retina ◽  
Protein Distribution ◽  
Optic Stalk ◽  
Retinal Tissue ◽  
Pax6 Protein ◽  
Signalling Molecule ◽  
Pax Family ◽  
In Cells

Pax6 and Pax2 are members of the Pax family of transcription factors that are both expressed in the developing visual system of zebrafish embryos. Pax6 protein is present in all cells that form the neural retina and pigment epithelium, whereas Pax2 is located primarily in cells that will give rise to the optic stalk. In this study, we have addressed the role of midline signalling in the regulation of Pax2 and Pax6 distributions and in the subsequent morphogenesis of the eyes. Midline signalling is severely perturbed in cyclops mutant embryos resulting in an absence of ventral midline CNS tissue and fusion of the eyes. Mutant embryos ectopically express Pax6 in a bridge of tissue around the anterior pole of the neural keel in the position normally occupied by cells that form the optic stalks. In contrast, Pax2 protein is almost completely absent from this region in mutant embryos. Concommitant with the changes in Pax protein distribution, cells in the position of the optic stalks differentiate as retina. These results suggest that a signal emanating from the midline, which is absent in cyclops mutant embryos, may be required to promote Pax2 and inhibit Pax6 expression in cells destined to form the optic stalks. Sonic hedgehog (Shh also known as Vhh-1 and Hhg-1) is a midline signalling molecule that is absent from the neuroepithelium of cyclops mutant embryos at early developmental stages. To test the possibility that Shh might be able to regulate the spatial expression of Pax6 and Pax2 in the optic primordia, it was overexpressed in the developing CNS. The number of cells containing Pax2 was increased following shh overexpression and embryos developed hypertrophied optic stalk-like structures. Complimentary to the changes in Pax2 distribution, there were fewer Pax6-containing cells and pigment epithelium and neural retina were reduced. Our results suggest that Shh or a closely related signalling molecule emanating from midline tissue in the ventral forebrain either directly or indirectly induces the expression of Pax2 and inhibits the expression of Pax6 and thus may regulate the partitioning of the optic primordia into optic stalks and retinal tissue.

scholarly journals Cholesterol homeostasis in the vertebrate retina: Biology and pathobiology

2020 ◽  
pp. jlr.TR120000979 ◽  
Author(s):  
Sriganesh Ramachandra Rao ◽  
Steven J. Fliesler
Keyword(s):  
De Novo ◽  
Current Knowledge ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Neural Retina ◽  
Cholesterol Homeostasis ◽  
Sterol Synthesis ◽  
Topic Area ◽  
Sterol Transport ◽  
Age Related

Cholesterol is a quantitatively and biologically significant constituent of all mammalian cell membrane, including those that comprise the retina. Retinal cholesterol homeostasis entails the interplay between de novo synthesis, uptake, intra-retinal sterol transport, metabolism and efflux. Defects in these complex processes are associated with several congenital and age-related disorders of the visual system. Herein, we provide an overview of the following topics: a) cholesterol synthesis in the neural retina; b) lipoprotein uptake and intraretinal sterol transport in the neural retina and the retinal pigment epithelium (RPE); c) cholesterol efflux from the neural retina and the RPE; and d) biology and pathobiology of defects in sterol synthesis and sterol oxidation in the neural retina and the RPE. We focus, in particular, on studies involving animal models of monogenic disorders pertinent to the above topics, as well as in vitro models using biochemical, metabolic, and omic approaches. We also identify current knowledge gaps as well as opportunities in the field that beg further research in this topic area.

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