Inhibitor of differentiation and DNA-binding (Id) proteins, Id1 to Id4, function in the regulation of cellular proliferation and differentiation. Id proteins have been shown to interact with bHLH proteins and other proteins involved in regulating cellular proliferation and differentiation, suggesting a widespread regulatory function. Id1-3 are known to be expressed in the prosensory domain of developing cochlea. However, the roles of Id genes in cochlear development are not fully elucidated. The deficiency of any of the Id1-3 genes individually has little effect on the cochlear development, and therefore the functional redundancy among these genes have been presumed to explain the absence of phenotype. Here, we show that conditional knockout of Id1/2/3 genes (Id TKO) causes major defects in morphogenesis and cellular patterning in the development of mammalian cochlea. Id TKO cochlea was 82% shorter than control, and both decreased proliferation and increased cell death caused the hypomorph. Sox2-positive prosensory domain was formed in Id TKO cochlea, but the formation of the medial-lateral (central-peripheral) axis was disturbed; the boundary between the medial and lateral compartments in the prosensory domain was partially doubled; the number of inner hair cells per unit length increased, and the number of outer hair cells decreased. Furthermore, the lateral non-sensory compartment expressing Bmp4 and Lmo3 was missing. Thus, the patterning of the lateral epithelium was more affected than the medial epithelium. These results suggested that Id genes are crucial for morphogenesis of the cochlea duct and patterning of the lateral epithelium in the developing cochlea. Further analyses by quantitative RT-PCR and immunostaining using cochlear explants with a Bmp pathway inhibitor revealed that the Bmp-Id pathway originates from the lateral non-sensory compartment and promotes outer hair cell differentiation.

分化抑制剂和DNA结合（Id）蛋白Id1至Id4在调节细胞增殖和分化中起作用。已经证明Id蛋白与bHLH蛋白和其他参与调节细胞增殖和分化的蛋白相互作用，提示其广泛的调节功能。Id1-3已知开发耳蜗prosensory域表达。但是，Id基因在耳蜗发育中的作用尚未完全阐明。任何Id1-3基因的缺乏对耳蜗的发育几乎没有影响，因此，推测这些基因之间的功能冗余可以解释表型的缺失。在这里，我们显示条件淘汰Id1 / 2/3基因（Id TKO）在哺乳动物耳蜗的发育中导致形态发生和细胞模式形成方面的重大缺陷。Id TKO耳蜗比对照组短82％，增殖减少和细胞死亡增加均引起亚型。在Id TKO耳蜗中形成了Sox2阳性的感觉区域，但内侧-中央（中央-外周）轴的形成受到干扰。感觉区域中内侧和外侧腔室之间的边界被部分加倍。每单位长度的内部毛细胞数量增加，而外部毛细胞数量减少。此外，外侧非感觉区室表达Bmp4和Lmo3失踪。因此，外侧上皮的图案比内侧上皮受到的影响更大。这些结果表明，Id基因对于耳蜗导管的形态发生和发育中的耳蜗的侧上皮细胞的形成至关重要。通过定量RT-PCR进行进一步分析，并使用带有Bmp途径抑制剂的人工耳蜗外植体进行免疫染色，发现Bmp-Id途径起源于外侧非感觉区室，并促进了外部毛细胞的分化。