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Retinal homeobox 1 is required for retinal neurogenesis and photoreceptor differentiation in embryonic zebrafish.

ABSTRACT: Retinal homeobox (Rx/Rax) genes are essential for the organogenesis of the vertebrate eye. These genes are dynamically expressed in a tissue-specific manner during eye development, suggesting pleiotropic roles. We use a temporally-selective gene knockdown approach to identify endogenous functions for the zebrafish rx genes, rx1 and rx2. Depletion of rx1 over the period of eye organogenesis resulted in severely reduced proliferation of retinal progenitors, the loss of expression of the transcription factor pax6, delayed retinal neurogenesis, and extensive retinal cell death. In contrast, depletion of rx2 over the same developmental time resulted in reduced expression of pax6 in the eye anlage, but only modest effects on retinal cell survival. Knockdown of rx1 specifically during photoreceptor development inhibited the expression of multiple photoreceptor-specific genes, while knockdown of rx2 over this time selectively inhibited the expression of a subset of these genes. Our findings support a function for rx2 in regulating pax6 within the optic primordia, a function for rx1 in maintaining the pluripotent, retinal progenitor cell state during retinal development, as well as selective functions for rx1 and rx2 in regulating photoreceptor differentiation.

SUBMITTER: Nelson SM

PROVIDER: S-EPMC2794694 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Retinal homeobox 1 is required for retinal neurogenesis and photoreceptor differentiation in embryonic zebrafish.

Nelson Steve M SM Park Leon L Stenkamp Deborah L DL

Developmental biology 20090110 1

Retinal homeobox (Rx/Rax) genes are essential for the organogenesis of the vertebrate eye. These genes are dynamically expressed in a tissue-specific manner during eye development, suggesting pleiotropic roles. We use a temporally-selective gene knockdown approach to identify endogenous functions for the zebrafish rx genes, rx1 and rx2. Depletion of rx1 over the period of eye organogenesis resulted in severely reduced proliferation of retinal progenitors, the loss of expression of the transcript ...[more]

PMID: 19210961

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Project description:The precise regulation of numbers and types of neurons through control of cell cycle exit and terminal differentiation is an essential aspect of neurogenesis. The Hippo signaling pathway has recently been identified as playing a crucial role in promoting cell cycle exit and terminal differentiation in multiple types of stem cells, including in retinal progenitor cells. When Hippo signaling is activated, the core Mst1/2 kinases activate the Lats1/2 kinases, which in turn phosphorylate and inhibit the transcriptional cofactor Yap. During mouse retinogenesis, overexpression of Yap prolongs progenitor cell proliferation, whereas inhibition of Yap decreases this proliferation and promotes retinal cell differentiation. However, to date, it remains unknown how the Hippo pathway affects the differentiation of distinct neuronal cell types such as photoreceptor cells. In this study, we investigated whether Hippo signaling regulates retinogenesis during early zebrafish development. Knockdown of zebrafish mst2 induced early embryonic defects, including altered retinal pigmentation and morphogenesis. Similar abnormal retinal phenotypes were observed in zebrafish embryos injected with a constitutively active form of yap [(yap (5SA)]. Loss of Yap's TEAD-binding domain, two WW domains, or transcription activation domain attenuated the retinal abnormalities induced by yap (5SA), indicating that all of these domains contribute to normal retinal development. Remarkably, yap (5SA)-expressing zebrafish embryos displayed decreased expression of transcription factors such as otx5 and crx, which orchestrate photoreceptor cell differentiation by activating the expression of rhodopsin and other photoreceptor cell genes. Co-immunoprecipitation experiments revealed that Rx1 is a novel interacting partner of Yap that regulates photoreceptor cell differentiation. Our results suggest that Yap suppresses the differentiation of photoreceptor cells from retinal progenitor cells by repressing Rx1-mediated transactivation of photoreceptor cell genes during zebrafish retinogenesis.

Dataset Information

Retinal homeobox 1 is required for retinal neurogenesis and photoreceptor differentiation in embryonic zebrafish.

Publications

Retinal homeobox 1 is required for retinal neurogenesis and photoreceptor differentiation in embryonic zebrafish.

Similar Datasets

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