Abstract
Neonatal mouse cochlear supporting cells have a limited ability to divide and trans-differentiate into hair cells, but this ability declines rapidly in the two weeks after birth. This decline is concomitant with the morphological and functional maturation of the organ of Corti prior to the onset of hearing. However, despite this association between maturation and loss of regenerative potential, little is known of the molecular changes that underlie these events. To identify these changes, we used RNA-seq to generate transcriptional profiles of purified cochlear supporting cells from 1- and 6-day-old mice. We found many significant changes in gene expression during this period, many of which were related to regulation of proliferation, differentiation of inner ear components and the maturation of the organ of Corti prior to the onset of hearing. One example of a change in regenerative potential of supporting cells is their robust production of hair cells in response to a blockade of the Notch signaling pathway at the time of birth, but a complete lack of response to such blockade just a few days later. By comparing our supporting cell transcriptomes to those of supporting cells cultured in the presence of Notch pathway inhibitors, we show that the transcriptional response to Notch blockade disappears almost completely in the first postnatal week. Our results offer some of the first molecular insights into the failure of hair cell regeneration in the mammalian cochlea.
Highlights
The death of auditory hair cells due to noise damage, ototoxins or aging is a principal cause of sensorineural hearing loss [1,2,3]
Summary of biological processes Gene Ontology (GO) terms that were significantly represented (p
The biological processes represented were obtained with the DAVID bioinformatics suite and summarized with the REVIGO tool
Summary
The death of auditory hair cells due to noise damage, ototoxins or aging is a principal cause of sensorineural hearing loss [1,2,3]. Neonatal mouse supporting cells are able to down-regulate cell cycle inhibitors, re-enter the cell cycle and generate hair cells in culture [8,9,10] This cell cycle re-entry can be driven by activation of the Wnt signaling pathway [11,12,13,14,15] or by deletion of cell cycle regulators such as p27Kip1 [16]. Ectopic activation of the hair cell-specific transcription factor Atoh in supporting cells can drive their differentiation into hair cells [12, 22,23,24] In all these cases, the capacity of mouse supporting cells to either divide or trans-differentiate into hair cells is lost between birth and the onset of hearing at two weeks of age [1, 9, 22, 23, 25]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have