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

Development. 2018 Nov 27;145(23):dev166579. doi: 10.1242/dev.166579.

Abstract

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.

Keywords: Hearing; Mouse; Notch; Plasticity; Regeneration; Wnt.

Publication types

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

MeSH terms

  • Animals
  • Animals, Newborn
  • Cell Proliferation
  • Cell Transdifferentiation
  • Cochlea / physiology*
  • Embryo, Mammalian / cytology
  • Epithelium / metabolism
  • Female
  • Gene Expression Regulation, Developmental
  • Hair Cells, Auditory / cytology
  • Hair Cells, Auditory / metabolism
  • Labyrinth Supporting Cells / cytology
  • Labyrinth Supporting Cells / metabolism
  • Male
  • Mammals / physiology*
  • Mice
  • Protein Stability
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Regeneration / genetics*
  • Reproducibility of Results
  • SOXB1 Transcription Factors / metabolism
  • TCF Transcription Factors / metabolism
  • Transcription, Genetic*
  • Wnt Signaling Pathway / genetics*
  • beta Catenin / metabolism

Substances

  • RNA, Messenger
  • SOXB1 Transcription Factors
  • TCF Transcription Factors
  • beta Catenin