ISL1 and POU4F1 directly interact to regulate the differentiation and survival of inner ear sensory neurons

作者：Mei Xu, Shuchun Li, Xiaoling Xie, Luming Guo, Dongliang Yu, Jiaping Zhuo, Jacey Lin, Lotem Kol, Lin Gan · 发表于：Journal of Neuroscience · 年份：2024 · DOI：10.1523/jneurosci.1718-23.2024 · 被引用次数：11 · 研究领域：Hearing, Cochlea, Tinnitus, Genetics、Congenital heart defects research、Cancer-related molecular mechanisms research

The inner ear sensory neurons play a pivotal role in auditory processing and balance control. Though significant progresses have been made, the underlying mechanisms controlling the differentiation and survival of the inner ear sensory neurons remain largely unknown. During development, ISL1 and POU4F transcription factors are co-expressed and are required for terminal differentiation, pathfinding, axon outgrowth and survival of neurons in the central and peripheral nervous systems. However, little is understood about their functional relationship and regulatory mechanism in neural development. Here, we have knocked out Isl1 or Pou4f1 or both in mice of both sexes. In the absence of Isl1 , the differentiation of cochleovestibular ganglion (CVG) neurons is disturbed and that Isl1 -deficient CVG neurons display defects in migration and axon pathfinding. Compound deletion of Isl1 and Pou4f1 causes a delay in CVG differentiation and results in a more severe CVG defect with a loss of nearly all of spiral ganglion neurons (SGNs). Moreover, ISL1 and POU4F1 interact directly in developing CVG neurons and act cooperatively as well as independently in regulating the expression of unique sets of CVG-specific genes crucial for CVG development and survival by binding to the cis -regulatory elements including the promoters of Fgf10 , Pou4f2 and Epha5 and enhancers of Eya1 and Ntng2 . These findings demonstrate that Isl1 and Pou4f1 are indispensable for CVG development and maintenance by ac...