A major cause of deafness disorders stem from the degeneration of hair cells within the inner ear although in many cases the mechanisms underlying these disorders is not understood. By defining the mechanisms controlling normal hair cell development, we will gain a better understanding of how these processes are disrupted in pathological situations and how the hair cells can be regenerated. The central hypothesis of this proposal is that the expression of the LIM-homeodomain transcription factor Isl1 provides the ventral cochlear epithelium with a competence to form the sensory organ and that the negative regulation of Isl1 function by the LIM-domain-only transcriptional regulators LMO3 and LMO4 restricts the competence to the presumptive OC (OC) region. In our preliminary studies, we have shown that during the sensory development in the cochlea at E12.5 to E16.5, Isl1 is expressed in a broad domain in the ventral cochlear epithelium, including the presumptive OC. Interestingly, the expression of LMO3 is detected in the lesser epithelial ridge (LER), whereas LMO4 expression is confined to the greater epithelial ridge (GER) and to the distal LER (dLER). The combined LMO3 and LMO4 expression domain overlaps with that of Isl1 except in the presumptive OC region where Isl1 is expressed alone. Consistent with our hypothesis, we have shown that loss of LMO4 results in the formation of supernumerary hair cells in the dLER, confirming a role for LMO4 as a negative regulator of sensory organ development. Thus, based on the established roles of LMO proteins in inhibiting LIM-HD proteins' function in transcriptional regulation, the combined action of Isl1, LMO3 and LMO4 could determine the formation of the OC region. In order to test this hypothesis and investigate the roles of LIM-domain factors in the inner ear development, we propose the following three specific aims: 1). To determine the requirement for LMO4 in the sensory and neuronal development in the cochlea and vestibule by targeted disruption of LMO4; 2). To determine whether the ectopic expression of LMO4 in the presumptive prosensory region represses the sensory development by the conditional activation of LMO4 expression in the Isl1-expressing cells; and 3). To determine the role of Isl1 in the sensory and neuronal development of the inner ear by the conditional deletion of Isl1.
Loss of the inner ear hair cells in the organ of Corti is the leading cause of hearing loss that affects 278 million people worldwide, including 28 million in the United States. However, since the loss of hair cells is an irreversible process and mammalian inner ear lacks the capability to regenerate hair cells, effective remedies to replace hair cells remain elusive. The studies proposed in this application will provide new insights into the molecular mechanisms underlying the sensory organ formation in the inner ear and could lead to novel approaches in the treatment and eventual cure of deafness by de novo hair cell regeneration. The central hypothesis of this proposal is that the expression of the LIM-homeodomain transcription factor provides the ventral cochlear epithelium with the competence to form the sensory organ and that the LIM-domain-only transcriptional regulators suppress the role of LIM-homeodomain factor in the ventral cochlea except the presumptive organ of Corti region. Thus, the combined function of LIM-homeodomain and LIM-domain-only factors regulates the competence in the ventral cochlear epithelium and determines the region of the presumptive organ of Corti. ? ? ?
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