Abstract
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.
Highlights
The neural retina (NR) and retinal pigment epithelium (RPE) arise from a common pool of progenitors during optic vesicle development
Optic vesicle progenitors express the same transcription factor-encoding genes, and signaling from surrounding tissues subsequently contributes to the regionalization of the optic vesicle into prospective RPE and NR domains
Yap/Taz-Tea domain (Tead) signaling is active during optic cup morphogenesis Analysis of the 4xGTIIC:d2GFP transgenic line (Miesfeld and Link, 2014) suggested a role for Yap/Taz-Tead activity in the developing lens, NR and RPE (Fig. 1; supplementary material Movie 2)
Summary
The neural retina (NR) and retinal pigment epithelium (RPE) arise from a common pool of progenitors during optic vesicle development. Heterozygous loss-of-function mutations in YAP1 in humans can result in autosomal dominant coloboma and a mutation within the Yap-binding domain of TEAD1 causes Sveinsson’s chorioretinal atrophy (SCRA), an autosomal dominant loss of RPE, choroid, and photoreceptors radiating from the optic nerve head (Fossdal et al, 2004; Williamson et al, 2014). These mutations and associated diseases have been described, the mechanism(s) underlying the defects is unknown. These tools revealed roles for the Yap and Taz transcriptional co-activators in choroid fissure closure and RPE specification that are likely to be conserved between zebrafish and humans
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