Notch signaling is critical for the development and survival of mammalian auditory supporting cells
Embargo until
2019-12-01
Date
2015-09-18
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Publisher
Johns Hopkins University
Abstract
The auditory sensory epithelium is critical for our ability to detect sound, and is composed of mechano-sensory hair cells and highly specialized glial-like supporting cells. Supporting cells provide structural and functional support to hair cells and play an essential role in cochlear development, homeostasis and repair. Despite their importance, little is known about the molecular mechanisms guiding supporting cell development. Previous studies revealed that the evolutionary conserved Notch signaling pathway plays an important role in the formation and maintenance of the common pool of hair cell and supporting cell progenitors (pro-sensory cells) while later during differentiation, Notch signaling becomes highly activated in a subset of pro-sensory cells destined to become supporting cells, inhibiting these cells from acquiring a hair cell fate. For the first time we provide evidence to support an instructive role for Notch signaling in supporting cell development. Using an unbiased genome wide approach we identified genes positively regulated by Notch signaling in the developing cochlea. We used genetic strategies to show that Notch signaling is both necessary and sufficient for the expression of the majority of these genes. We used two different genetic mouse models to disrupt canonical Notch signaling in differentiating supporting cells and found that Notch signaling is critical for the survival of supporting cells. Additionally we showed that a reduction in canonical Notch signaling results in defects in the proper innervation of the cochlea. Finally, we provide evidence that the different roles of canonical Notch signaling during supporting cell development are mediated by different Notch signaling components.
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Keywords
Development, Cochlea