Modulation of Wnt and Notch Signalling Pathways for Sensory Hair Cell Regeneration in the Mammalian Auditory Organ

I investigated the temporal pattern and underlying mechanisms of the transient regenerative response to canonical Wnt activation in the neonatal mouse cochlea. Ectopic Wnt activation in vitro in typically quiescent embryonic day (E) 13.5 and postnatal day (P) 0 cochleae promoted prosensory and supporting cell proliferation, respectively; however, this effect was no longer observed at P5. This age-dependent decline in proliferative capacity occurred despite similar levels of β-catenin accumulation in cochleae following transient exposure to the Wnt activator at all three developmental stages, suggesting that barriers to Wnt-mediated regeneration lie downstream of β-catenin stabilization and might be related to a lack of key transcription factors or limited access to downstream target genes. Furthermore, maintaining Wnt activation in early neonatal stages promoted changes in the expression of specific Wnt and Notch pathway genes and extended the window for hair cell induction in response to Notch signalling inhibition.M.Sc.2020-11-15 00:00:0