The goal of this project is to characterize regulatory networks that drive neurosensory precursor cell development and differentiation in the inner ear. Specification and proliferation of otic epithelial precursor cells and the decision to become distinct cell types are crucial events during inner ear development. The instructions for these processes are encoded in the genome - in non-coding regulatory sequences. These control gene expression programs in time and space by interacting with transcription factors, cofactors and chromatin regulators to create and maintain specific cell states. Although many important genes have been identified in the inner ear, the network of factors and gene interactions that dictate the specialized phenotypes of differentiated cells during inner ear development are not understood. We found that the chromatin remodeling protein BRG1, the central enzymatic subunit in the SWI/SNF chromatin remodeling machinery, is necessary for initiating neuronal developmental program by interacting with inner ear neurosensory cell-specific transcription factors EYA1 and SIX1 in gain-of-function studies in cochlear explants and 3T3 fibroblast cells. However, no studies have yet been performed to directly address the developmental roles of SWI/SNF chromatin remodelers in the inner ear. While chromatin remodelers provide an important mechanism for gene transcription, the DNA regulatory elements/enhancers that regulate inner ear development and function are not defined. Our preliminary data clearly show that Brg1 plays a critical role in inner ear morphogenesis. In this application, we propose to define the developmental roles of Brg1 in neurosensory precursor cell development and differentiation and address whether Brg1 defines enhancers required to promote neuronal and sensory cell identity. The experiments proposed in this study have the potential to provide new insight into how a network of factors and gene interactions constitute the program that drives otic epithelial cell development towards functional sensory neurons or hair cells. Identifying genes and regulatory networks that control sensory or neuronal-cell specific gene expression program should provide valuable insights into the genetic networks that underlie congenital neurosensory deficits.

Public Health Relevance

Hearing loss is the most frequent sensory defect in humans and about one in 1,000 children is affected by severe deafness at birth or during early childhood. This grant proposes to elucidate how a small group of progenitor cells are induced to become functional sensory neurons and hair cells in the inner ear. Identifying genes and regulatory networks that control sensory or neuronal-cell specific gene expression program should provide valuable insights into the genetic networks that underlie congenital neurosensory deficits.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC014718-03
Application #
9414013
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2016-02-01
Project End
2021-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Genetics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Xu, Jinshu; Ueno, Hiroo; Xu, Chelsea Y et al. (2017) Identification of mouse cochlear progenitors that develop hair and supporting cells in the organ of Corti. Nat Commun 8:15046
Zhang, Ting; Xu, Jinshu; Maire, Pascal et al. (2017) Six1 is essential for differentiation and patterning of the mammalian auditory sensory epithelium. PLoS Genet 13:e1006967
Wong, Elaine Y M; Xu, Chelsea Y; Brahmachary, Manisha et al. (2016) A Novel ENU-Induced Mutation in Myo6 Causes Vestibular Dysfunction and Deafness. PLoS One 11:e0154984