The goal of the Section on Developmental Neuroscience is to identify the cellular, molecular and genetic factors that play a role in the development of the sensory epithelium of the mammalian cochlea, the organ of Corti. The organ of Corti is comprised of a highly rigorous pattern of specialized cell types that has been shown to be required for normal hearing. During the last year, members of the laboratory concentrated on several different issues related to the development of the organ of Corti. The cochlea develops as an outpocketing from the ventral region of the otocyst that extends to between 1.5 and 3.5 turns depending on the species. In the mouse, the cells that will give rise to the organ of Corti are all present within the duct by E14, even though the cochlea will not obtain its mature length until P0. As a result, the cells that comprise the organ of Corti must undergo significant cellular rearrangements between these time points. To begin to examine these changes, we determined the cellular patterns and number of cell contacts for cells within the developing cochlea at different developmental time points. Results indicate that the epithelium becomes patterned in a gradient that begins in the base of the cochlea and extends along its length. As development proceeds, cells become aligned in rows and the number of contacts per cell begins to decrease. In addition, labeling of small groups of cells within the cochlea indicates that redistribution along the length of the cochlea also plays a role in the development of this cellular pattern. Previous results from our laboratory and other laboratories had identified the basic helix-loop-helix transcription factor (bHLH) Math1 as a key regulator of the development of mechanosensory hair cells. However the factors that regulate the expression of Math1 are poorly understood. To begin to identify genetic factors that could play a role in regulating the expression of Math1 within the cochlea, we examined the expression of members of the ID gene family. ID genes have been shown to negatively regulate expression of bHLH genes by competitively binding to a necessary dimer partner. Our results indicate the ID1 and ID3 are expressed in the developing ear and that the pattern of expression correlates with negative regulation of Math1. Based on these results it seems likely that ID genes can play a role in the regulation of Math1 within the cochlea. One of the most intriguing cell types in the organ of Corti are the pillar cells. These cells comprise a double-row that extends along the length of the cochlea. Previous work from our laboratory had identified a member of the fibroblast growth factor receptor signaling family, FGFR3, as a key regulator of pillar cell differentiation. This year, we examined the potential role of FGFR3 in pillar cell commitment by generating FGFR3 hyperactivity through treatment with two ligands for FGFR3, fibroblast growth factor 2 (FGF2) or FGF17. In both cases, increased activation of FGFR3 lead to an increase in the number of cells that developed as pillar cells. This result suggests that the normally limited number of pillar cells may be regulated through the presence of limiting amounts of FGF ligand within the epithelium. In addition, preliminary results suggest that FGF ligands may be expressed by a single cell type within the cochlea, suggesting that inductive interactions between cell types may play a key role in cellular patterning within the cochlea.
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