The development of the organ of Corti is a tightly regulated process, in which a small "prosensory" domain of the cochlear duct is sorted into various types of hair cells and support cells. While it known that intercellular signals, like Notch and FGF, are required at several steps in cochlear development, their precise roles and relationship at the stage of sensory cell specification are not clear. In the past year, we have found that FGF20 is necessary for sensory cell specification. Inhibition of FGF20 or inhibition of the FGF receptors leads to a loss in Atoh1 expression. We have also found that inhibition of Notch signaling in explant cultures at early stages of cochlear development leads to a block in sensory cell development. These findings have led to a working model in which the prosensory Notch signal leads to the expression of Fgf20, which then activates Atoh1 in the sensory cells. In this submission, we propose several lines of investigation aimed at testing specific hypotheses about the molecular mechanisms of sensory cell specification. Our proposal has the following specific aims: 1. To determine whether the prosensory action of Notch is mediated by FGF20;2. To determine whether the action of Notch on FGF20 expression is direct;3. To determine whether Ets domain transcription factors are necessary and/or sufficient for sensory cell specification. A better understanding of the molecular pathways regulating normal development will be critical for rational strategies for hair cell replacement and regeneration in adult onset deafness.

Public Health Relevance

Understanding how the sensory cells of the inner ear are specified is a very important first step towards designing rational repair strategies for use after damage due to ototoxicity or noise. This proposal is geared towards elucidating the key steps in development of the sensory cells and the molecules involved. Once the molecular pathways, and the order in which they are used, are established it would allow for testing of compounds that activate or inhibit these pathways in damaged tissue to assess their influence on regeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC009991-05
Application #
8642626
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Freeman, Nancy
Project Start
2010-04-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
5
Fiscal Year
2014
Total Cost
$341,462
Indirect Cost
$135,762
Name
University of Washington
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Chai, Renjie; Xia, Anping; Wang, Tian et al. (2011) Dynamic expression of Lgr5, a Wnt target gene, in the developing and mature mouse cochlea. J Assoc Res Otolaryngol 12:455-69
Bermingham-McDonogh, Olivia; Reh, Thomas A (2011) Regulated reprogramming in the regeneration of sensory receptor cells. Neuron 71:389-405
Hartman, Byron H; Reh, Thomas A; Bermingham-McDonogh, Olivia (2010) Notch signaling specifies prosensory domains via lateral induction in the developing mammalian inner ear. Proc Natl Acad Sci U S A 107:15792-7