Tan Jaime, Duron Alicia, Sucov Henry M, Makita Takako
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
iScience. 2024 Dec 24;28(1):111680. doi: 10.1016/j.isci.2024.111680. eCollection 2025 Jan 17.
Mutations in the human genes encoding the endothelin ligand-receptor pair and cause Waardenburg-Shah syndrome (WS4), which includes congenital hearing impairment. The current explanation for auditory dysfunction is defective migration of neural crest-derived melanocytes to the inner ear. We explored the role of endothelin signaling in auditory development in mice using neural crest-specific and placode-specific mutation plus related genetic resources. On an outbred strain background, we find a normal representation of melanocytes in hearing-impaired mutant mice. Instead, our results in neural crest-specific mutants implicate a previously unrecognized role for glial support of synapse assembly between auditory neurons and cochlear hair cells. Placode-specific mutation also caused impaired hearing, resulting from deficient synaptic transmission. Our observations demonstrate the significant influence of genetic modifiers in auditory development, and invoke independent and separable roles for endothelin signaling in the neural crest and placode lineages to create a functional auditory circuitry.
编码内皮素配体 - 受体对的人类基因发生突变会导致瓦登伯革 - 沙阿综合征（WS4），该综合征包括先天性听力障碍。目前对听觉功能障碍的解释是神经嵴衍生的黑素细胞向内耳的迁移存在缺陷。我们利用神经嵴特异性和基板特异性突变以及相关遗传资源，探究了内皮素信号在小鼠听觉发育中的作用。在远交系背景下，我们发现在听力受损的突变小鼠中黑素细胞的分布正常。相反，我们在神经嵴特异性突变体中的研究结果表明，神经胶质对听觉神经元和耳蜗毛细胞之间突触组装的支持作用此前未被认识到。基板特异性突变也导致听力受损，这是由于突触传递不足所致。我们的观察结果证明了遗传修饰因子在听觉发育中的重大影响，并揭示了内皮素信号在神经嵴和基板谱系中具有独立且可分离的作用，以构建功能性听觉回路。
