The avian inner ear is a dynamic model for studying the growth and development of excitation in auditory and vestibular hair cells. The underlying basis for excitation is membrane proteins that form ion channels. The acquisition of these channels is important for modulating auditory and vestibular excitation during development. Moreover, as in the visual system, excitation may """"""""sculpt"""""""" the auditory systems. However, a fundamental unanswered question about these proteins is, what mechanisms regulate their expression? The acquisition of ion channels can be governed by extrinsic variables that include metabolites and proteins. Included among these molecules are retinoids and neurotrophins that bind to receptors and turn on intracellular pathways in differentiating hair cells. The neurotrophins can regulate the fate of presumptive cells of the inner ear by stimulating high (Trk) and low affinity (p75NTR) receptors. This stimulation may induce cell proliferation, death, differentiation, and potentially, the transcription of genes that encode potassium currents, such as the A-type current in hair cells. Retinoids contribute to this regulation by modulating the neurotrophin effect. The long-term objectives of this project are to understand how extrinsic factors regulate ion channel expression from an age when cells of the inner ear are morphologically undifferentiated to when they become hair cells. The experiments presented in this proposal will specifically examine: (1) candidate genes that encode the transient A-type potassium channel in hair cells, (2) expression and distribution of candidate genes in the embryo and adult sensory epithelium, (3) expression of the Trk and p75 neurotrophin receptors during development in vivo and in vitro, and (4) regulation of potassium current and candidate gene expression by neurotrophins and their intracellular messengers. The knowledge gathered from the proposed experiments will contribute to our understanding of the regulatory mechanisms that control ion channel genes in sensory cells of the inner ear. This knowledge is relevant to understanding how excitatory signals in sensory cells contribute to the normal and abnormal development of the auditory and vestibular systems.
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