Yap is essential for retinal progenitor cell cycle progression and RPE cell fate acquisition in the developing mouse eye

Abstract

Yap functions as a transcriptional regulator by acting together with sequence-specific DNA binding factors and transcription cofactors to mediate cell proliferation in developing epithelial tissues and tumors. An upstream kinase cascade controls nuclear localization and function in response to partially identified exogenous signals, including cell-to-cell contact. Nevertheless, its role in CNS development is poorly understood. In order to investigate Yap function in developing CNS, we characterized the cellular outcomes after selective Yap gene ablation in developing ocular tissues. When Yap was lost, presumptive retinal pigment epithelium acquired anatomical and molecular characteristics resembling those of the retinal epithelium rather than of RPE, including loss of pigmentation, pseudostratified epithelial morphology and ectopic induction of markers for retinal progenitor cells, like Chx10, and neurons, like β-Tubulin III. In addition, developing retina showed signs of progressive degeneration, including laminar folding, thinning and cell loss, which resulted from multiple defects in cell proliferation and survival, and in junction integrity. Furthermore, Yap-deficient retinal progenitors displayed decreased S-phase cells and altered cell cycle progression. Altogether, our studies not only illustrate the canonical function of Yap in promoting the proliferation of progenitors, but also shed new light on its evolutionarily conserved, instructive role in regional specification, maintenance of junctional integrity and precise regulation of cell proliferation during neuroepithelial development.

A CTGF-YAP regulatory pathway is essential for angiogenesis and barriergenesis in the retina

“…6H). These gene targets are under either direct or indirect regulation by YAP (Kim et al, 2016;Kim et al, 2015b), suggesting that YAP acts as a relay for CTGF-dependent control of EC growth.…”

Hippo‐Yap/Taz signaling: Complex network interactions and impact in epithelial cell behavior

“…By contrast, a report in Yap‐deficient mice showed defects in proliferation and survival as well as evidence of progenitor cell transdifferentiation into NR. As shown by the appearance of NR markers, such as Chx10 and b‐tubulin III, (J. Y. Kim et al, ). It is unclear whether this disparity represents species‐specific differences in ocular development RPE.…”

“…Zhao et al, 2014). However, TEADs are widely recognized as the most common Yap interaction partners in the contexts of development, cancer, and epithelial-mesenchymal transition (Hiemer et al, 2014;Ivanek et al, 2014;J. Y. Kim et al, 2016;Mahoney, Mori, Szymaniak, Varelas, & Cardoso, 2014;Miesfeld et al, 2015;Stein et al, 2015;Y.…”

“…As shown by the appearance of NR markers, such as Chx10 and b-tubulin III, (J. Y. Kim et al, 2016). It is unclear whether this disparity represents species-specific differences in ocular development RPE.…”

YAP and TAZ, the conductors that orchestrate eye development, homeostasis, and disease

“…Kim et al, 2016). The YAP-deficient phenotype in mice illustrates YAP multiple indispensable roles in cell cycle control, angiogenic activation, progenitor proliferation, junctional integrity maintenance, regional fate choice, and structural preservation (Choi et al, 2015;J. Y. Kim et al, 2016;H.…”