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. 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 specific role of Math1 has not been determined. In particular, while deletion of Math1 results in an absence of hair cells, it is not clear whether supporting cells, another important cell type within the organ of Corti, are also affected. To examine this possibility, cochleae were obtained from animals containing a targeted mutation in Math1. The presence of supporting cells in these cochleae was then analyzed using a combination of morphological and molecular techniques. Results indicated that development of supporting cells is significantly disrupted in Math1 mutants. These results suggest that Math1 regulates the development of multiple cell types within the developing cochlea. In a separate series of experiments we examined the role of vangl2 in the generation of uniform orientation of stereociliary bundles within the cochlea. All mechanosensory hair cells have a specialized bundle of actin-based cilia, referred to as stereocilia, located on the luminal surface of the cell. Deflection of this bundle in a particular direction is perceived by that cell as sound. However, each hair cell is sensitive only to deflections of the bundle in a single direction. Therefore, the establishment of appropriate directional orientation of each bundle is crucially important for function. Based on the role of a homologous gene in the fruitfly, Drosophila melanogaster, we examined the role of vangl2 using a mouse model containing a spontaneous mutation in vangl2. Results indicated that the orientations of stereociliary bundles were significantly disrupted in cochleae from vangl2 mutants. Moreover, we also demonstrated that a second gene, scrb1, also plays a role in the generation of uniform stereociliary bundle orientation. These results represent the first identification of genes that regulate stereociliary bundle orientation. Based on these results it should be possible to identify other genes and proteins that interact with vangl2 and scrb1 in the generation of uniform bundle orientation. Additional experiments are underway to determine if either of these genes mat act as deafness genes within the human population.
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