Department of Cell Biology & Neuroscience
W. M. Keck Center for Collaborative Neuroscience
604 Allison Road
Piscataway, NJ 08854
Molecular basis of hair cell regeneration
Hearing loss is a common sensory disorder affecting approximately 17% of American adults. The origins of deafness range from inherited genetic defects to noise-induced trauma, but auditory neuropathy due to spiral ganglion neuron (SGN) loss is of particular concern. No routine treatment is available for SGN loss, but stem cell replacement therapy is a promising method to alleviate auditory neuropathy. Robust functional recovery requires stem cell derived neurons to attain the proper morphology, axonal targeting and synaptic specificity. Few engrafted stem cell derived neurons show this potential and some even develop into inappropriate cell types or teratomas that reduce the therapeutic efficacy of stem cell replacement. Identifying genes that facilitate differentiation of stem cells into SGNs will aid regeneration. My lab uses inner ear development as a roadmap to identify factors that may promote SGN regeneration.
During inner ear development, SGNs arise from a progenitor pool that progressively acquires specialized neuronal properties. As progenitors develop, they express combinatorial set of transcription factors (TF) to specify SGN cell fate, promote differentiation and maturation. Within each transcriptional network, TFs influence each other's expression, while activating specific gene expression programs that underlie each differentiation event. In addition to the transcriptional regulatory networks, epigenetic changes affect developmental events. We are interested in how the epigenetic changes during development of SGNs affect the transcriptional regulatory networks and development of SGNs. In particular, we are interested in the chromodomain helicase DNA binding protein 7 (Chd7). Chd7 is an ATP dependent nucleosome repositioning protein. Mutations in human Chd7 causes CHARGE syndrome. Among the constellation of clinical features observed in patients with CHARGE are ear anomalies. The inner ear abnormalities observed in animal lacking Chd7 include improper development of SGNs. Using a combination of fate-restricted otic cell lines and mouse models, we are currently seeking to understand the molecular underpinnings of Chd7 function in SGN development.