Thursday, December 26, 2024
12/26/2024
PROJECT SUMMARY Sensorineural deafness is typically caused by the irreversible loss of the inner ear hair cells (HCs). Currently, there is no treatment available to reverse the loss of HCs. Recent advance in regenerative medicine offers promise in treating sensorineural deafness through HC regeneration. Elucidating the molecular mechanism underlying the formation of the inner ear HCs will aid our effort to regenerate HCs and restore hearing. During early cochlear development, the partially overlapping expression of GATA3, ISL1, ISL2, and their negative regulators, LMO3 and LMO4, suggests a novel model for the regulation of cochlear duct patterning and sensory formation, in which the expression of GATA3, ISL1, and ISL2 makes the ventral cochlear epithelium competent to form the sensory region and the expression LMO3 and LMO4 suppresses the transcriptional activity of ISL1, ISL2, and GATA3 in all but the presumptive prosensory domain. Consistent with this model, we have shown that targeted deletion of Lmo4 leads to the formation of an ectopic organ of Corti completed with inner and outer HCs and supporting cells in the presumptive external sulcus. Loss of Lmo4 also results in a broader expression domain of CDKN1B, a cyclin-dependent kinase inhibitor and an early marker of the developing sensory organ. Conversely, deletion of Gata3 impairs the formation of the sensory domain and leads to the loss of CDKN1B expression. Interestingly, our preliminary study showed that while loss of Isl1 or Isl2 alone has no significant effect on the formation of prosensory domain, compound Isl1/Isl2-null mutation abolishes the CDKN1B-expressing prosensory domain, suggesting that Isl1 and Isl2 could function redundantly in specifying prosensory region. To further understand the role and mechanism of ISL1 and ISL2 in determining the prosensory domain in the cochlea, we will knock out Isl2 and Isl1/Isl2 specifically in the inner ear and assess the effect on cochlear duct patterning and sensory formation. In addition, we will knock out Lmo3 and Lmo4 specifically in the inner ear and investigate their function during cochlear duct patterning and sensory formation. To understanding the underlying functional mechanism, we will use RNA-Seq, snRNA- Seq/snATAC-Seq, and CUT&Tag technologies to identify candidate genes that are directly controlled by ISL1, ISL2, and GATA3 in the ventral cochlear epithelium. Together, this study will provide significant information about the molecular events underlying sensorineural deafness, accelerate the discovery of novel sensorineural deafness genes, and aid our effort to regenerate inner ear HCs to restore hearing. Additionally, elucidating the novel interaction among the LIM-HD, LMO, and GATA proteins will advance our knowledge of their roles in the development and pathogenesis of the inner ear and other tissues.
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