The Hippo pathway controls a switch between retinal progenitor cell proliferation and photoreceptor cell differentiation in zebrafish.
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.
Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Yoichi
Y
Asaoka
Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Shoji
S
Hata
Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Misako
M
Namae
Centre for Regenerative Medicine, Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath, United Kingdom.
Makoto
M
Furutani-Seiki
Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Hiroshi
H
Nishina
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics* / Q000502:physiology; D049109:Cell Proliferation / Q000235:genetics* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics; D010786:Photoreceptor Cells / Q000502:physiology*; D010858:Pigmentation / Q000235:genetics / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012160:Retina / Q000502:physiology*; D012243:Rhodopsin; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics; D015027:Zebrafish / Q000235:genetics* / Q000502:physiology; D029961:Zebrafish Proteins / Q000235:genetics*; D000099317:Hippo Kinases
D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D012243:Rhodopsin; D000090742:Serine-Threonine Kinase 3; D014157:Transcription Factors; D029961:Zebrafish Proteins; C541414:stk3 protein, zebrafish; D000099317:Hippo Kinases