Transcriptional response to Wnt activation regulates the regenerative capacity of the mammalian cochlea.

Autor:	Samarajeewa A; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto ON, M5S 1A8, Canada., Lenz DR; Department of Otolaryngology, Harvard Medical School, Boston, MA 02114, USA.; Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA., Xie L; Biological Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto ON, M4N 3M5, Canada.; Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning Guangxi, 530021, China., Chiang H; Department of Otolaryngology, Harvard Medical School, Boston, MA 02114, USA.; Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA., Kirchner R; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA., Mulvaney JF; Biological Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto ON, M4N 3M5, Canada., Edge ASB; Department of Otolaryngology, Harvard Medical School, Boston, MA 02114, USA.; Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, MA 02114, USA., Dabdoub A; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto ON, M5S 1A8, Canada alain.dabdoub@sri.utoronto.ca.; Biological Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto ON, M4N 3M5, Canada.; Department of Otolaryngology - Head & Neck Surgery, University of Toronto, Toronto ON, M5G 2C4, Canada.
Jazyk:	angličtina
Zdroj:	Development (Cambridge, England) [Development] 2018 Nov 27; Vol. 145 (23). Date of Electronic Publication: 2018 Nov 27.
DOI:	10.1242/dev.166579
Abstrakt:	Lack of sensory hair cell (HC) regeneration in mammalian adults is a major contributor to hearing loss. In contrast, the neonatal mouse cochlea retains a transient capacity for regeneration, and forced Wnt activation in neonatal stages promotes supporting cell (SC) proliferation and induction of ectopic HCs. We currently know little about the temporal pattern and underlying mechanism of this age-dependent regenerative response. Using an in vitro model, we show that Wnt activation promotes SC proliferation following birth, but prior to postnatal day (P) 5. This age-dependent decline in proliferation occurs despite evidence that the Wnt pathway is postnatally active and can be further enhanced by Wnt stimulators. Using an in vivo mouse model and RNA sequencing, we show that proliferation in the early neonatal cochlea is correlated with a unique transcriptional response that diminishes with age. Furthermore, we find that augmenting Wnt signaling through the neonatal stages extends the window for HC induction in response to Notch signaling inhibition. Our results suggest that the downstream transcriptional response to Wnt activation, in part, underlies the regenerative capacity of the mammalian cochlea. Competing Interests: Competing interestsThe authors declare no competing or financial interests. (© 2018. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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