Although there are several sources of vestibular dysfunction, many causes such as viral disorders, antibiotic toxicity, autoimmune disease, and degenerative disorders can all result in hair cell loss. Complete recovery may be possible for these individuals through regeneration of missing vestibular hair cells. Morphological differences between hair cells in different regions of the vestibular maculae enable them to respond to specific aspects of motion, and are necessary for normal vestibular function. These variations are likely to be regulated by transcription factors, and reflect the regional patterning of individal sensory organs. The research goal of this proposal is to identify regional differences in transcription factor expression, and determine how these genes contribute to hair cell heterogeneity. One aspect of regional variation is the division of both the utricle and saccule int two regions with oppositely oriented stereocilia. We have utilized a transgenic mouse line to segregate these two populations, and have identified a set of transcription factors with differences in regional expression by RNA-seq. I will analyze the spatial and temporal expression patterns of these transcription factors and further characterize their cell type expression. The function of these genes will be interrogated by both overexpression in vitro and by analyzing knock-out mice. This assay will assess the role of these genes in stereociliary bundle orientation, changes in gene expression, and alterations in afferent innervation. The proposed study will allow us to validate regional variations in transcription factor expression, shed light on the function of these genes, establish a molecular research background in the candidate, and help the applicant move toward an independent, productive, fulfilling career.
The heterogeneity of sensory hair cells of the inner ear underlies the broad detection of sound and motion. This project is designed to determine some of the genes necessary for one aspect of this heterogeneity, stereocilia bundle orientation. By understanding the normal developmental events leading to differences in hair cells we can identify targets for therapeutic intervention, and potentially regenerate region specific hair cell.
|Duncan, Jeremy S; Stoller, Michelle L; Francl, Andrew F et al. (2017) Celsr1 coordinates the planar polarity of vestibular hair cells during inner ear development. Dev Biol 423:126-137|