The cochlea contains two types of mechanosensory receptor cells, inner (IHC) and outer (OHC) hair cells, which play very different, but critical, roles in hearing. Cochlear hair cells arise during embryogenesis, but how they specifically differentiate into IHCs or OHCs remains unknown. We found a presumed transcription factor (INSM1) expressed in incipient OHCs, but not in IHCs, during mouse embryogenesis. Insm1 is the first gene found to be uniquely expressed in nascent, early differentiating OHCs (but not IHCs). We find that ablating Insm1 affects OHCs and will elucidate its role in OHC differentiation. We hypothesize that INSM1 acts by regulating (either activating or repressing) other genes early in OHC differentiation and will identify these target genes. Finally, we will take advantage of a unique reporter line (Insm1GFP::Cre) that selectively labels OHCs from their onset to cell sort and identify genes and proteins uniquely or preferentially expressed in embryonic OHCs or IHCs. We will then functionally test some of these genes for roles in OHC- and IHC-specific development. These approaches offer for the first time the means to elucidate how cochlear OHCs and IHCs differentiate their unique features. This knowledge will be critical for the development of therapies to restore hearing due to hair cell death, as this will require the specific replacement of OHCs, IHCs or both.
The leading cause of hearing loss is the death of cochlear outer hair cells (OHCs), and since these cells are not produced after birth, current attempts to restore hearing involve stem cell or related technologies to replace lost OHCs. However, we presently have no knowledge of the critical factors required to generate an OHC as opposed to an inner hair cell, the other hair cell type in the cochlea. Our studies will lead to the identification of genes required to generate OHCs vs IHCs, and hence could be instrumental in the development of regenerative approaches aimed at reversing loss of hearing due to death of OHCs.
| Wiwatpanit, Teerawat; Lorenzen, Sarah M; Cantú, Jorge A et al. (2018) Trans-differentiation of outer hair cells into inner hair cells in the absence of INSM1. Nature 563:691-695 |
| Wiwatpanit, Teerawat; Remis, Natalie N; Ahmad, Aisha et al. (2018) Codeficiency of Lysosomal Mucolipins 3 and 1 in Cochlear Hair Cells Diminishes Outer Hair Cell Longevity and Accelerates Age-Related Hearing Loss. J Neurosci 38:3177-3189 |
