Specific ablation of Hippo signalling component Yap1 in retinal progenitors and Müller cells results in late onset retinal degeneration

Abstract

Yes-associated protein (YAP) is a major component of the Hippo pathway involved in development, growth, repair and homeostasis. Nonsense YAP1 mutations in humans result in autosomal dominant coloboma. Here, we generated a conditional knockout mouse model in which Yap1 was specifically deleted in embryonic retinal progenitor cells (RPCs) and in mature Müller cells using a Chx10-Cre driver. Our data demonstrated that the conditional ablation of Yap1 in embryonic RPCs does not prevent normal retinal development and caused no gross changes in retinal structure during embryonic and early postnatal life. Nevertheless, Yap1 deficient in retinal Müller cells in adult mice leads to impaired visual responses and extensive late-onset retinal degeneration, characterized by reduced cell number in all retinal layers. Immunofluorescence data further revealed the degeneration and death of rod and cone photoreceptors, bipolar cells, horizontal cells, amacrine cells and ganglion cells to varying degrees in aged knockout mice. Moreover, alteration of glial homeostasis and reactive gliosis were also observed. Finally, cell proliferation and TUNEL assay revealed that the broad retinal degeneration is mainly caused by enhanced apoptosis in late period. Together, this work uncovers that YAP is essential for the normal vision and retinal maintenance, highlighting the crucial role of YAP in retinal function and homeostasis.

Special issue: Cilia and ciliopathies

“…This special issue also contains five original research articles reporting studies of ciliary signaling and function in different organisms as well as human patients. Yang et al (2022) report the role of Hippo signaling during retina development. Removal of YAP1, specifically in the retinal Muller cells, causes extensive late‐onset retinal degeneration, including cone and rod photoreceptors that have the highly specialized connecting cilium.…”