In this project, we propose to study novel mechanisms governing the decision of cell fate between the sensory and non-sensory epithelium of mouse cochlear duct. We have recently shown that (1) high levels of Bone Morphogenetic Protein (BMP) signaling induce the outer sulcus, (2) moderate levels of BMP signaling are required for the prosensory domain destined to form the organ of Corti, and (3) BMP signaling suppresses K?lliker's organ.
In Specific Aim 1 we will explore an interaction between BMP and transcription factors in the outer sulcus. We discovered that disruption of a BMP type I receptor, Bmpr-Ia (Alk3) causes a broadening of the prosensory domain in a mirror-duplicated pattern at the expense of the outer sulcus. A similar phenotype is observed in Jackson circler mice in which a Six-binding protein, Jxc1 is mutated. We will analyze Jackson circler mutant cochlea in vivo and in cochlear organ culture morphologically and biochemically to investigate molecular mechanisms of the specification of the outer sulcus.
In Specific Aim 2 we will determine the roles of Fgf10 signaling in the development of the stria vascularis and Reissner's membrane. We observed that the stria vascularis and Reissner's membrane are significantly smaller or missing in the Fgf10-deficient cochlea at E18.5. We will further analyze the Fgf10 mutant cochlea to investigate whether Fgf10 promotes the differentiation of the stria vascularis and Reissner's membrane. Using cochlear organ cultures, we will also test whether the addition of BMP4 promotes the expression of Fgfr2 and the differentiation of the stria vascularis and Reissner's membrane synergistically with Fgf10 signaling.
In Specific Aim 3 we will determine whether noncanonical BMP signaling is required for the development of the non-sensory structures of the cochlear duct. We have shown that the outer sulcus, the stria vascularis and Reissner's membrane are altered in the absence of BMP signaling. However, canonical and noncanonical BMP signaling pathways are differently activated in these tissues. We propose to determine whether a balance between canonical and noncanonical BMP signaling pathways is critical for the cell fate determination and survival of the outer sulcus, th stria vascularis and Reissner's membrane. We will inactivate and activate noncanonical BMP signaling by deleting intracellular components, Tak1 and Tab1 in the mouse, as well as by biochemical treatments in cell lines. Our proposed research will significantly contribute to the understanding of the key mechanisms that control the cell fate decision of all sensory and non-sensory cell types in the mammalian cochlea.

Public Health Relevance

This proposal aims to study molecular mechanisms that generate a core structure of hearing organ, the cochlea. By using the mouse as a model system, we will investigate key mechanisms to regenerate auditory cells from stem cells such as induced pluripotent stem cells for the restoration of hearing.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Auditory System Study Section (AUD)
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Freeman, Nancy
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University of Southern California
Schools of Medicine
Los Angeles
United States
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