Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 1, Pages 166-171Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1415901112
Keywords
Notch1; beta-catenin; proliferation; hair cells; inner ear
Categories
Funding
- 973 Program [2011CB504506, 2015CB965000]
- National Natural Science Foundation of China [81230019, 81400463, 81470687, 81470692, 81371094]
- Construction Program of Shanghai Committee of Science and Technology [12DZ2251700, 14DJ1400203]
- Major Program of Shanghai Committee of Science and Technology [11441901000]
- Frederick & Ines Yeatts Hair Cell Regeneration Grant
- David-Shulsky Foundation
- Bertarelli Foundation
- NIH [R01 DC06908]
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The activation of cochlear progenitor cells is a promising approach for hair cell (HC) regeneration and hearing recovery. The mechanisms underlying the initiation of proliferation of postnatal cochlear progenitor cells and their transdifferentiation to HCs remain to be determined. We show that Notch inhibition initiates proliferation of supporting cells (SCs) and mitotic regeneration of HCs in neonatal mouse cochlea in vivo and in vitro. Through lineage tracing, we identify that a majority of the proliferating SCs and mitotic-generated HCs induced by Notch inhibition are derived from the Wnt-responsive leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5(+)) progenitor cells. We demonstrate that Notch inhibition removes the brakes on the canonical Wnt signaling and promotes Lgr5(+) progenitor cells to mitotically generate new HCs. Our study reveals a new function of Notch signaling in limiting proliferation and regeneration potential of postnatal cochlear progenitor cells, and provides a new route to regenerate HCs from progenitor cells by interrupting the interaction between the Notch and Wnt pathways.
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