Faculty Collaboration Database

Yap and Taz regulate retinal pigment epithelial cell fate. Development 2015 Sep 01;142(17):3021-32

Date

07/26/2015

Pubmed ID

26209646

Pubmed Central ID

PMC4582179

DOI

10.1242/dev.119008

Scopus ID

2-s2.0-84940754780 (requires institutional sign-in at Scopus site)   113 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 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.

Author List

Miesfeld JB, Gestri G, Clark BS, Flinn MA, Poole RJ, Bader JR, Besharse JC, Wilson SW, Link BA

Authors

Michael Andrew Flinn Postdoctoral Fellow in the Physiology department at Medical College of Wisconsin
Brian A. Link PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Joel Bryan Miesfeld PhD Assistant Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Alleles
Animals
Apoptosis
Cell Lineage
Cell Nucleus
Cell Proliferation
Coloboma
DNA-Binding Proteins
Epithelial Cells
Gene Expression Regulation, Developmental
Genes, Reporter
HEK293 Cells
Humans
Intracellular Signaling Peptides and Proteins
Morphogenesis
Mutation
Nuclear Proteins
Phenotype
Protein Binding
RNA, Messenger
Retinal Pigment Epithelium
Signal Transduction
Trans-Activators
Transcription Factors
Transgenes
Up-Regulation
Zebrafish
Zebrafish Proteins