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. Over the past five years, a model of this process has emerged, primarily through analysis of mice with mutations in developmentally expressed genes. The prosensory region, defined by p27 expression, is specified by the Notch pathway ligand, Jagged1, FGF receptor 1, and the transcription factor Sox2. Following specification, hair cells and supporting cells are defined within this region by a process that requires Math1, a bHLH transcription factor, and the additional Notch ligands, Jagged2 and Dll1. A final stage in the process of development of the organ of Corti again requires FGF signaling, this time through FGFR3, to direct a subset of the support cells to develop as pillar cells. While this model has received strong experimental support, there are still many unanswered questions. For example, FGF signaling is known to be critical for pillar cell development, but we have recently found that mutants in Fgfr3 also have an increase in outer hair cells. Our recent results further suggest that there may be an interaction between FGF signaling and another key regulator of hair cell development, the Notch pathway, but we know almost nothing about connections between these pathways. In our screens for other FGFs and other Notch pathway components that might play a role in cochlear development, we discovered that FGF20 is expressed in a highly specific pattern that coincides with the prosensory domain from E14 to E16 and that Hes related genes, Hesr1 and Hesr2, are expressed in this same domain, from E12.5. In this proposal we address these questions in three Specific Aims.
Aim 1. Determine the role of FGF signaling and FGF20 in early cochlear development.
Aim 2. Determine whether Hesr1 and Hesr2 are the downstream effectors of Jagged1/Notch.
Aim 3. Determine whether Prox1 directly regulates expression of Fgfr3 in support cells of the developing organ of Corti? We will use a combination of molecular biological techniques, as well as analysis of transgenic and knockout mice, to accomplish these aims. Understanding the roles of the FGF and Notch pathways in cochlear development may lead to the design of treatments for congenital disorders. Moreover, 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.
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| Munnamalai, Vidhya; Hayashi, Toshinori; Bermingham-McDonogh, Olivia (2012) Notch prosensory effects in the Mammalian cochlea are partially mediated by Fgf20. J Neurosci 32:12876-84 |
| Bermingham-McDonogh, Olivia; Reh, Thomas A (2011) Regulated reprogramming in the regeneration of sensory receptor cells. Neuron 71:389-405 |
| Hayashi, Toshinori; Lamba, Deepak A; Slowik, Amber et al. (2010) A method for stabilizing RNA for transfection that allows control of expression duration. Dev Dyn 239:2034-40 |
| Hartman, Byron H; Nelson, Branden R; Reh, Thomas A et al. (2010) Delta/notch-like EGF-related receptor (DNER) is expressed in hair cells and neurons in the developing and adult mouse inner ear. J Assoc Res Otolaryngol 11:187-201 |
| 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 |
| Hayashi, Toshinori; Ray, Catherine A; Younkins, Christa et al. (2010) Expression patterns of FGF receptors in the developing mammalian cochlea. Dev Dyn 239:1019-26 |
| Hayashi, Toshinori; Kokubo, Hiroki; Hartman, Byron H et al. (2008) Hesr1 and Hesr2 may act as early effectors of Notch signaling in the developing cochlea. Dev Biol 316:87-99 |
| Hayashi, Toshinori; Ray, Catherine A; Bermingham-McDonogh, Olivia (2008) Fgf20 is required for sensory epithelial specification in the developing cochlea. J Neurosci 28:5991-9 |
| Hartman, Byron H; Hayashi, Toshinori; Nelson, Branden R et al. (2007) Dll3 is expressed in developing hair cells in the mammalian cochlea. Dev Dyn 236:2875-83 |
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