This proposal aims to study the novel functions of bone morphogenetic protein (BMP) signaling in pattern formation of mouse cochlea. We have recently shown (1) high levels of BMP signaling induce the outer sulcus, (2) moderate levels of BMP signaling is required for the prosensory domain destined to form the organ of Corti, and (3) BMP signaling suppresses K""""""""lliker's organ.
Specific Aim 1 will determine 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. Similar phenotype is observed in Jackson circler mice in which a Six-binding protein, Jxc1 is mutated. We will perform analysis of Jackson circler mutant cochlea, cochlear organ culture and biochemical analysis to investigate molecular mechanisms of the specification of the outer sulcus.
Specific Aim 2 will determine an interaction between BMP and FGF signaling during prosensory specification. Previous studies have shown that K""""""""lliker's organ is capable of producing sensory hair cells when a transcription factor, Atoh1 is ectopically expressed. For further seeking the potential of drug discovery to restore auditory hair cells, a precise control of extracellular signaling would be key to producing auditory hair cells from non-sensory cells such as those from the outer sulcus and K""""""""lliker's organ. We will test whether modulation of BMP and FGF signaling pathways mediates a fate decision between K""""""""lliker's organ and organ of Corti cells by using cochlear organ culture and analysis of Alk3;Fgf10 compound mutant mice.
Specific Aim 3 will determine whether noncanonical BMP signaling is required for the development of non-sensory structures of the cochlear duct. We have shown the outer sulcus, 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 and survival of the outer sulcus, 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 cochlear organ culture. Our proposed research will exert an influence on the understanding of the key mechanisms that control the cell fate of all types of sensory and non-sensory cells 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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Shibata, Shumei; Miwa, Toru; Wu, Hsiao-Huei et al. (2016) Hepatocyte Growth Factor-c-MET Signaling Mediates the Development of Nonsensory Structures of the Mammalian Cochlea and Hearing. J Neurosci 36:8200-9
Urness, Lisa D; Wang, Xiaofen; Shibata, Shumei et al. (2015) Fgf10 is required for specification of non-sensory regions of the cochlear epithelium. Dev Biol 400:59-71