Yap and Taz regulate retinal pigment epithelial cell fate

Joel B. Miesfeld, Gaia Gestri, Brian S. Clark, Michael A. Flinn, Richard J. Poole, Jason R. Bader, Joseph C. Besharse, Stephen W. Wilson, Brian A. Link

Research output: Contribution to journalArticlepeer-review

90 Scopus citations

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 Teadresponsive 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 Yapdependent 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 dosagedependent 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.

Original languageEnglish
Pages (from-to)3021-3032
Number of pages12
JournalDevelopment (Cambridge)
Volume142
Issue number17
DOIs
StatePublished - Sep 1 2015

Keywords

  • Choroid fissure
  • Coloboma
  • Directed differentiation of stem cells
  • Eye development
  • Hippo signaling
  • Ocular morphogenesis
  • Sveinsson’s chorioretinal atrophy
  • Tfec
  • Zebrafish

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