YAP MEDIATES HAIR CELL REGENERATION IN BALANCE ORGANS OF CHICKENS, BUT LATS KINASES SUPPRESS ITS ACTIVITY IN MICE
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Date
2020-05-13
Authors
Rudolf, Mark A.
Andreeva, Anna
Kozlowski, Mikolaj M.
Kim, Christina E.
Moskowitz, Bailey A.
Anaya-Rocha, Alejandro
Kelley, Matthew W.
Corwin, Jeffrey T.
Journal Title
Journal ISSN
Volume Title
Publisher
Society for Neuroscience
Abstract
Loss of sensory hair cells causes permanent hearing and balance deficits in humans and other mammals, but for nonmammals such deficits are temporary. Nonmammals recover hearing and balance sensitivity after supporting cells proliferate and
differentiate into replacement hair cells. Evidence of mechanical differences between those sensory epithelia and their supporting cells prompted us to investigate whether the capacity to activate YAP, an effector in the mechanosensitive Hippo
pathway, correlates with regenerative capacity in acceleration-sensing utricles of chickens and mice of both sexes. After hair
cell ablation, YAP accumulated in supporting cell nuclei in chicken utricles and promoted regenerative proliferation, but YAP
remained cytoplasmic and little proliferation occurred in mouse utricles. YAP localization in supporting cells was also more
sensitive to shape change and inhibition of MST1/2 in chicken utricles than in mouse utricles. Genetic manipulations showed
that in vivo expression of the YAP-S127A variant caused robust proliferation of neonatal mouse supporting cells, which produced progeny that expressed hair cell markers, but proliferative responses declined postnatally. Expression of YAP-5SA,
which more effectively evades inhibitory phosphorylation, resulted in TEAD-dependent proliferation of striolar supporting
cells, even in adult utricles. Conditional deletion of LATS1/2 kinases abolished the inhibitory phosphorylation of endogenous
YAP and led to striolar proliferation in adult mouse utricles. The findings suggest that damage overcomes inhibitory Hippo
signaling and facilitates regenerative proliferation in nonmammalian utricles, whereas constitutive LATS1/2 kinase activity
suppresses YAP-TEAD signaling in mammalian utricles and contributes to maintaining the proliferative quiescence that
appears to underlie the permanence of sensory deficits.
Key words: hair cell; Hippo; LATS; regeneration; utricle; YAP
Description
Keywords
hair cell, Hippo, LATS, regeneration, utricle, YAP, Type of access: Open Access
Citation
Rudolf, M. A., Andreeva, A., Kozlowski, M. M., Kim, C. E., Moskowitz, B. A., Anaya-Rocha, A., Kelley, M. W., & Corwin, J. T. (2020). YAP Mediates Hair Cell Regeneration in Balance Organs of Chickens, But LATS Kinases Suppress Its Activity in Mice. The Journal of Neuroscience, 40(20), 3915–3932. https://doi.org/10.1523/jneurosci.0306-20.2020