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. To determine the specific effects of Math1, we generated an inducible form of Math1 that was then used to transiently express Math1 in the greater epithelial ridge, a population of epithelial cells within the cochlea that have been shown to be able to develop as hair cells under some circumstances. Transient activation of Math1 in these cells induced the formation of clusters of sensory epithelia that contained both hair cells and associated non-sensory supporting cells. However, while development of hair cells required expression of Math1, supporting cells could develop from either cells expressing Math1, or adjacent cells that did not express Math1. These results demonstrated that inductive interactions between adjacent cells play a key role in regulating cell fate and the formation of the sensory epithelium within the cochlea. In addition, subsequent experiments demonstrated that individual cells utilized the Notch signaling pathway to sort themselves into hair cells and supporting cells. Specifically, as a subset of cells within clusters of cells that transiently expressed Math1 began to develop as hair cells, these cells began to express Jagged2, a ligand that binds to and activates the Notch receptor in neighboring cells. As a result of this interaction, cells with activation Notch were inhibited from developing as hair cells. The results of the experiments described above suggested that a key step in development of the cochlear mosaic is the decision to maintain Math1 expression, and therefore to develop as a hair cell. However the factors that bias some cells towards the hair cell fate are not clear. In an effort to determine some of these factors, we examined the expression of a class of molecules called Ids (for inhibitors of differentiation). Ids play an important role in regulating the overall level of Math1 activity within a single cell. Interestingly, Ids inhibit Math1 activity, so cells with more Id expression are less likely to develop as hair cells. An analysis of Id expression in the cochlea indicated that Ids are down-regulated in those cells that will develop as hair cells. Moreover, forced expression of Ids within single cells within the cochlea leads to a significant inhibition of hair cell development. These results strongly suggest that expression of Ids plays a key role in the determination of which cells will develop as hair cells.
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