Outer and Inner Hair Cell Development

项目摘要 耳蜗含有两种类型的机械感觉感受器细胞，即内(IHC)和外(OHC)毛细胞， 它们在听力中扮演着截然不同但至关重要的角色。耳蜗毛细胞在胚胎发育过程中产生，但如何产生 它们具体区分为IHC或OHC仍不清楚。我们发现了一个推测的转录因子 在小鼠胚胎发育过程中，(INSM1)在早期的毛细胞中表达，而在间质细胞中不表达。Insm1是第一个基因 发现在新生的、早期分化的毛细胞中唯一表达(但不是IHC)。我们发现这是一种消融 Insm1影响OHC，并将阐明其在OHC分化中的作用。我们假设INSM1的作用方式是 在OHC分化早期调节(激活或抑制)其他基因，并将识别这些靶点 基因。最后，我们将利用唯一的报告程序行(Insm1GFP：：CRE)来选择性地标记来自 它们起病到细胞分类和鉴定在胚胎OCs中唯一或优先表达的基因和蛋白质 或者IHC。然后，我们将从功能上测试其中一些基因在OHC和IHC特异性发育中的作用。 这些方法首次提供了阐明耳蜗腺上皮细胞和内耳毛细胞如何区分的方法。 它们的独特之处。这一知识对于开发恢复听力的治疗方法至关重要，因为 毛细胞死亡，因为这将需要具体更换毛细胞和/或毛细胞。

Project Summary The cochlea contains two types of mechanosensory receptor cells, inner (IHC) and outer (OHC) hair cells, which play very different, but critical, roles in hearing. Cochlear hair cells arise during embryogenesis, but how they specifically differentiate into IHCs or OHCs remains unknown. We found a presumed transcription factor (INSM1) expressed in incipient OHCs, but not in IHCs, during mouse embryogenesis. Insm1 is the first gene found to be uniquely expressed in nascent, early differentiating OHCs (but not IHCs). We find that ablating Insm1 affects OHCs and will elucidate its role in OHC differentiation. We hypothesize that INSM1 acts by regulating (either activating or repressing) other genes early in OHC differentiation and will identify these target genes. Finally, we will take advantage of a unique reporter line (Insm1GFP::Cre) that selectively labels OHCs from their onset to cell sort and identify genes and proteins uniquely or preferentially expressed in embryonic OHCs or IHCs. We will then functionally test some of these genes for roles in OHC- and IHC-specific development. These approaches offer for the first time the means to elucidate how cochlear OHCs and IHCs differentiate their unique features. This knowledge will be critical for the development of therapies to restore hearing due to hair cell death, as this will require the specific replacement of OHCs, IHCs or both.