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      Morphogenesis and axis specification occur in parallel during optic cup and optic fissure formation, differentially modulated by BMP and Wnt

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          Abstract

          Optic cup morphogenesis is an intricate process. Especially, the formation of the optic fissure is not well understood. Persisting optic fissures, termed coloboma, are frequent causes for congenital blindness. Even though the defective fusion of the fissure margins is the most acknowledged reason for coloboma, highly variable morphologies of coloboma phenotypes argue for a diverse set of underlying pathomechanisms. Here, we investigate optic fissure morphogenesis in zebrafish to identify potential morphogenetic defects resulting in coloboma. We show that the formation of the optic fissure depends on tissue flow movements, integrated into the bilateral distal epithelial flow forming the optic cup. On the temporal side, the distal flow translates into a ventral perpendicular flow, shaping the temporal fissure margin. On the nasal side, however, the distal flow is complemented by tissue derived from the optic stalk, shaping the nasal fissure margin. Notably, a distinct population of TGFβ-signalling positive cells is translocated from the optic stalk into both fissure margins. Furthermore, we show that induced BMP signalling as well as Wnt-signalling inhibition result in morphogenetic defects of the optic fissure. Our data also indicate that morphogenesis is crucial for a proper positioning of pre-specified dorsal–ventral optic cup domains.

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          Early eye development in vertebrates.

          This review provides a synthesis that combines data from classical experimentation and recent advances in our understanding of early eye development. Emphasis is placed on the events that underlie and direct neural retina formation and lens induction. Understanding these events represents a longstanding problem in developmental biology. Early interest can be attributed to the curiosity generated by the relatively frequent occurrence of disorders such as cyclopia and anophthalmia, in which dramatic changes in eye development are readily observed. However, it was the advent of experimental embryology at the turn of the century that transformed curiosity into active investigation. Pioneered by investigators such as Spemann and Adelmann, these embryological manipulations have left a profound legacy. Questions about early eye development first addressed using tissue manipulations remain topical as we try to understand the molecular basis of this process.
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            Beta-catenin controls differentiation of the retinal pigment epithelium in the mouse optic cup by regulating Mitf and Otx2 expression.

            The retinal pigment epithelium (RPE) consists of a monolayer of cuboidal, pigmented cells that is located between the retina and the choroid. The RPE is vital for growth and function of the vertebrate eye and improper development results in congenital defects, such as microphthalmia or anophthalmia, or a change of cell fate into neural retina called transdifferentiation. The transcription factors microphthalmia-associated transcription factor (Mitf) and orthodenticle homolog 2 (Otx2) are crucial for RPE development and function; however, very little is known about their regulation. Here, by using a Wnt-responsive reporter, we show that the Wnt/beta-catenin pathway is activated in the differentiating mouse RPE. Cre-mediated, RPE-specific disruption of beta-catenin after the onset of RPE specification causes severe defects, resulting in microphthalmia with coloboma, disturbed lamination, and mislocalization of adherens junction proteins. Upon beta-catenin deletion, the RPE transforms into a multilayered tissue in which the expression of Mitf and Otx2 is downregulated, while retina-specific gene expression is induced, which results in the transdifferentiation of RPE into retina. Chromatin immunoprecipitation (ChIP) and luciferase assays indicate that beta-catenin binds near to and activates potential TCF/LEF sites in the Mitf and Otx2 enhancers. We conclude that Wnt/beta-catenin signaling is required for differentiation of the RPE by directly regulating the expression of Mitf and Otx2. Our study is the first to show that an extracellular signaling pathway directly regulates the expression of RPE-specific genes such as Mitf and Otx2, and elucidates a new role for the Wnt/beta-catenin pathway in organ formation and development.
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              Yap and Taz regulate retinal pigment epithelial cell fate

              The optic vesicle comprises a pool of bi-potential progenitor cells from which the retinal pigment epithelium (RPE) and neural retina fates segregate during ocular morphogenesis. Several transcription factors and signaling pathways have been shown to be important for RPE maintenance and differentiation, but an understanding of the initial fate specification and determination of this ocular cell type is lacking. We show that Yap/Taz-Tead activity is necessary and sufficient for optic vesicle progenitors to adopt RPE identity in zebrafish. A Tead-responsive transgene is expressed within the domain of the optic cup from which RPE arises, and Yap immunoreactivity localizes to the nuclei of prospective RPE cells. yap (yap1) mutants lack a subset of RPE cells and/or exhibit coloboma. Loss of RPE in yap mutants is exacerbated in combination with taz (wwtr1) mutant alleles such that, when Yap and Taz are both absent, optic vesicle progenitor cells completely lose their ability to form RPE. The mechanism of Yap-dependent RPE cell type determination is reliant on both nuclear localization of Yap and interaction with a Tead co-factor. In contrast to loss of Yap and Taz, overexpression of either protein within optic vesicle progenitors leads to ectopic pigmentation in a dosage-dependent manner. Overall, this study identifies Yap and Taz as key early regulators of RPE genesis and provides a mechanistic framework for understanding the congenital ocular defects of Sveinsson's chorioretinal atrophy and congenital retinal coloboma.
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                Author and article information

                Journal
                Open Biol
                Open Biol
                RSOB
                royopenbio
                Open Biology
                The Royal Society
                2046-2441
                February 2019
                13 February 2019
                13 February 2019
                : 9
                : 2
                : 180179
                Affiliations
                [1 ]Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg , 79104 Freiburg, Germany
                [2 ]Faculty of Biology, University of Freiburg , Schaenzlestrasse 1, 79104 Freiburg, Germany
                [3 ]Centre for Organismal Studies, Heidelberg University , 69120 Heidelberg, Germany
                Author notes

                Electronic supplementary material is available online at https://dx.doi.org/10.6084/m9.figshare.c.4381817.

                Author information
                http://orcid.org/0000-0001-7374-8886
                Article
                rsob180179
                10.1098/rsob.180179
                6395882
                1fe34031-75ab-4306-9ae7-26ca303c0da8
                © 2019 The Authors.

                Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.

                History
                : 24 September 2018
                : 7 January 2019
                Funding
                Funded by: HBiGGs;
                Funded by: Forschungskommission University Freiburg;
                Award ID: HEE1079/16
                Funded by: German Research Foundation (DFG) and the University of Freiburg in the funding programme Open Access Publishing;
                Categories
                58
                133
                Research
                Research Article
                Custom metadata
                February 2019

                Life sciences
                optic cup,optic fissure,morphogenesis,bmp,wnt,coloboma
                Life sciences
                optic cup, optic fissure, morphogenesis, bmp, wnt, coloboma

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