title: Yap and Taz regulate retinal pigment epithelial cell fate.
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.
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Joel B
authors.initials: JB
authors.lastname: Miesfeld
authors.affiliation: Department of Cell and Developmental Biology, UCL, London WC1E 6BT, UK.
authors.forename: Gaia
authors.initials: G
authors.lastname: Gestri
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Clark
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Flinn
authors.affiliation: Department of Cell and Developmental Biology, UCL, London WC1E 6BT, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Poole
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Bader
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Besharse
authors.affiliation: Department of Cell and Developmental Biology, UCL, London WC1E 6BT, UK.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Wilson
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA blink@mcw.edu.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Link
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D019070:Cell Lineage; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D003103:Coloboma / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009024:Morphogenesis / Q000235:genetics; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology* / Q000637:transplantation; D015398:Signal Transduction / Q000235:genetics; D000091262:TEA Domain Transcription Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D019076:Transgenes; D015854:Up-Regulation; D000091102:YAP-Signaling Proteins; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D000091262:TEA Domain Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C000612287:WWTR1 protein, zebrafish; D000091102:YAP-Signaling Proteins; C583457:Yes-associated protein (yap), zebrafish; D029961:Zebrafish Proteins; C506512:tead1a protein, zebrafish
keywords: Choroid fissure; Coloboma; Directed differentiation of stem cells; Eye development; Hippo signaling; Ocular morphogenesis; Sveinsson's chorioretinal atrophy; Tfec; Zebrafish