Abstract
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.
Highlights
In the vertebrate embryonic nervous system, multipotent neural progenitor cells proliferate and differentiate into diverse neuronal and glial cell types that eventually build up functional neural circuits such as the retina [1,2]
Mst2 is Required for Early Embryogenesis in Zebrafish To unravel the role of Hippo signaling in early zebrafish development, we first examined whether zebrafish mst functions during early embryogenesis
The predicted amino acid sequence of the protein encoded by the zebrafish mst2 gene is approximately 90% identical to the sequences of the human and mouse Mst2 proteins, and contains the evolutionarily conserved autophosphorylation site and SARAH domain that are important for Mst activation (Fig. S1A)
Summary
In the vertebrate embryonic nervous system, multipotent neural progenitor cells proliferate and differentiate into diverse neuronal and glial cell types that eventually build up functional neural circuits such as the retina [1,2]. During the course of retinal development, retinal progenitor cells (RPCs) either continue to proliferate or exit mitosis and differentiate into various neuronal cell types. This process is tightly regulated and ensures that the proper numbers and types of differentiated cells needed to assemble a functional retinal circuitry are produced [1,2]. A fundamental mystery in retinal development has been the identity of the molecular mechanism controlling the developmental switch between RPC self-renewal and differentiation. Aspects of retinal morphogenesis and histology, as well as the molecular components governing retinal development, are highly conserved between zebrafish and mammals
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