Cellular proliferation through Yap by inhibition of Lats kinases
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 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 Müller glia in human 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, some supporting cells move their nuclei into the hair-cell layer and express genes characteristic of hair cells. 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, and may thus contribute to the restoration of hearing through regenerative therapy.
Left: In the utricle of a mature mouse, essentially no proliferation is marked by incorporation of EdU. Right: Treatment with the Lats inhibitor causes massive labeling with EdU (white), which signifies extensive proliferation of supporting cells.
