The lens-corneal separation requires precision control of Hippo-Yap signaling

Abstract

Purpose : The Hippo-Yap signaling pathway is implicated in tissue development and homeostasis. In the lens, Yap is required for the maintenance of the lens progenitor pool, but it is not clear whether this is due to Yap’s function as a transcriptional activator or as part of the cell junction complex. In this study, we aim to investigate the role of Hippo-Yap signaling network and its mechanism in regulating murine lens development.

Methods : We generated both conditional knockout and conditional transgenic mouse models using Le-cre, which is specifically expressed in the lens progenitors. Immunofluorescence was performed to characterize the lens phenotype.

Results : Consistent with a previous study, genetic ablation of Yap resulted in substantial loss of the lens epithelium (LE) compartment at embryonic day 13 (E13). This LE defect could be rescued by expression of nuclear Yap (Yap^5SA), which is resistant to serine phosphorylation induced by Hippo signaling. In addition, expression of nuclear Yap led to ectopic expression of LE markers in the lens fiber compartment in a cell autonomous manner, suggesting that the nuclear but not the membrane function of Yap is responsible for maintenance of the lens progenitor property. Interestingly, the Yap^5SA-expressing lens remained connected to the surface ectoderm (which later develops into the cornea) and formed persistent lens stalk, indicating that Yap signaling is involved in the lens vesicle separation. Moreover, genetic ablation of Hippo signaling kinases mammalian STE20-like kinase (MST) and large tumor suppressor (LATS) recapitulated Yap gain of function (Yap^5SA) lens stalk phenotype.

Conclusions : Our study demonstrated that the nuclear function of Yap is both necessary and sufficient to maintain the lens progenitor pool. However, the level of active nuclear Yap must be tightly controlled by Hippo Signaling to ensure separation of the lens vesicle from the surface ectoderm. Suppression of Hippo signaling leads to the lens-corneal separation defect, which mimics Peters Anomaly in humans, suggesting that the Hippo-Yap signaling may underlie congenital lens disease.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.