Hippo signaling is an evolutionarily conserved pathway that restricts organ growth during development and suppresses regeneration in mature organs. Using a high-throughput phenotypic screen, we have identified a potent, non-toxic, and reversible inhibitor of Hippo signaling. An ATP-competitive inhibitor of Lats kinases, the compound causes Yap-dependent proliferation of murine supporting cells in the inner ear, murine cardiomyocytes, and human Müller glia in retinal organoids. RNA sequencing indicates that the substance fosters both the G1-S and G2-M checkpoint transitions and yields supporting cells capable of transdifferentiation. Upon withdrawal of the compound, a subset of supporting cells move their nuclei into the hair-cell layer and express genes characteristic of hair cells. Viral transfection of Atoh1 induces the expression of hair cell-specific proteins in progeny. The compound promotes the initial stages of the proliferative regeneration of hair cells, a process thought to be permanently suppressed in the adult mammalian inner ear.

Read more »