The peripheral auditory neuroepithelium contains both the differentiated receptor hair cells and associated supporting cells which appear morphologically much-less differentiated, and from which hair cells are thought to derive. A remarkable manifestation of hair cell differentiation is the presence of gradients in hair cell properties both along the tonotopic axis of the cochlea and across the receptor epithelium. These gradients in hair cell properties correlate with receptor function in important ways which are only beginning to be understood. The signals responsible for the developmental establishment and maintenance of these patterns of hair cell heterogeneity are unknown, but are critical to the function of the peripheral auditory apparatus as an effective frequency analyzer. One of the most direct demonstrations of hair cell physiologic heterogeneity is the measurement of potassium currents in hair cells from the chick receptor epithelium (basilar papilla). At least three potassium currents, an inwardly rectifying current (I-IR), a calcium-activated outward current (I-K(Ca)), and an inactivating voltage-gated current (I- A), are expressed in distinct and sometimes partially-overlapping populations of hair cells along and across the chick basilar papilla. These differences in hair cell properties must reflect, at some level, differences in gene expression. The long-term objective of these studies is to determine how the peripheral hearing receptor epithelium is able to establish and maintain the precise patterns of gene expression which underlie the observed gradients in hair cell physiologic properties. This goal will be approached using the potassium channels as molecular markers for the hair cells and hair cell subpopulations in the chick basilar papilla.
The specific aims are: l) To identify those channel molecules responsible for the three differentially-expressed currents by cloning the relevant cDNAs from the chick receptor. 2) To test the hypothesis that the gradients in current expression are determined by differential transcription of channel genes. This possibility will be distinguished from alternative levels of regulation using the specific cloned channel cDNA probes and specific antibodies raised against synthetic channel peptides to determine the spatial distributions of the channel transcripts and channel proteins, respectively. 3) To test the hypothesis that specific channel expression is limited to differentiated hair cells by determining whether these channels are also expressed in supporting cells. If supporting cells also express these channels, how are the spatial patterns of expression of the three channels in supporting cells related to their patterns of expression in hair cells. 4) To test the related hypothesis that signals determining the pattern of hair cell heterogeneity are present in the mature cochlea by determining if regenerating hair cells express, if only transiently, channels 'inappropriate' for their location on the basilar papilla. The successful accomplishment of these aims should help in the development of a model for how the auditory receptor epithelium is able to generate and maintain the critical patterns of hair cell heterogeneity. Such a model will be important in designing therapeutic approaches to the treatment of disorders of hearing.
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