Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway

Proc Natl Acad Sci U S A. 2015 Jan 6;112(1):166-71. doi: 10.1073/pnas.1415901112. Epub 2014 Dec 22.

Abstract

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.

Keywords: Notch1; hair cells; inner ear; proliferation; β-catenin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Lineage
  • Cell Proliferation
  • Hair Cells, Auditory / cytology*
  • Hair Cells, Auditory / metabolism*
  • Labyrinth Supporting Cells / metabolism
  • Mice
  • Mitosis*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Notch / antagonists & inhibitors
  • Receptors, Notch / metabolism*
  • SOXB1 Transcription Factors / metabolism
  • Wnt Signaling Pathway*

Substances

  • Lgr5 protein, mouse
  • Receptors, G-Protein-Coupled
  • Receptors, Notch
  • SOXB1 Transcription Factors