Hedgehog signaling regulates prosensory cell properties during the basal-to-apical wave of hair cell differentiation in the mammalian cochlea
Hedgehog signaling regulates prosensory cell properties during the basal-to-apical wave of hair cell differentiation in the mammalian cochlea
复制标题
DOI：
10.1242/dev.095398
复制
发表时间：
2013-09-15
期刊：
影响因子：
4.6
通讯作者：
Kageyama, Ryoichiro
中科院分区：
文献类型：
--
作者：
Tateya, Tomoko;Imayoshi, Itaru;Kageyama, Ryoichiro
机械感觉毛细胞和支持细胞从位于发育中的耳蜗上皮的前感觉域中的共同前体发育而来。前感觉细胞分化成毛细胞或支持细胞的收益从基底到顶端区域的耳蜗，但这种基底到顶端波的分化的机制和意义仍有待阐明。在这里，我们研究了刺猬（Hh）信号在耳蜗发育中的作用，通过检查体内Hh信号的上调和下调的影响。Hh效应smoothened（Smo）的基因激活或失活，特别是在发育中的耳蜗上皮后，prosensory域形成。表达Smo的组成型活性等位基因的耳蜗显示只有一排内毛细胞，没有外毛细胞（OHC）;异常未分化的前列腺样细胞存在于侧隔室，而不是OHC及其相邻的支持细胞。这表明Hh信号抑制前感觉细胞分化为毛细胞或支持细胞，并保持其作为前感觉细胞的特性。相反，在耳蜗与Smo条件敲除（Smo CKO），毛细胞分化优先加速在顶端区域。Smo CKO小鼠出生后存活，并表现出顶端区域毛细胞排列紊乱、毛细胞数量减少和听力受损。这些结果表明，Hh信号延迟毛细胞和支持细胞分化的顶端区域，形成的基底-顶端波的发展，并需要适当的分化，排列和生存的毛细胞和听力能力。
Mechanosensory hair cells and supporting cells develop from common precursors located in the prosensory domain of the developing cochlear epithelium. Prosensory cell differentiation into hair cells or supporting cells proceeds from the basal to the apical region of the cochleae, but the mechanism and significance of this basal-to-apical wave of differentiation remain to be elucidated. Here, we investigated the role of Hedgehog (Hh) signaling in cochlear development by examining the effects of up-and downregulation of Hh signaling in vivo. The Hh effector smoothened (Smo) was genetically activated or inactivated specifically in the developing cochlear epithelium after prosensory domain formation. Cochleae expressing a constitutively active allele of Smo showed only one row of inner hair cells with no outer hair cells (OHCs); abnormal undifferentiated prosensory-like cells were present in the lateral compartment instead of OHCs and their adjacent supporting cells. This suggests that Hh signaling inhibits prosensory cell differentiation into hair cells or supporting cells and maintains their properties as prosensory cells. Conversely, in cochlea with the Smo conditional knockout (Smo CKO), hair cell differentiation was preferentially accelerated in the apical region. Smo CKO mice survived after birth, and exhibited hair cell disarrangement in the apical region, a decrease in hair cell number, and hearing impairment. These results indicate that Hh signaling delays hair cell and supporting cell differentiation in the apical region, which forms the basal-to-apical wave of development, and is required for the proper differentiation, arrangement and survival of hair cells and for hearing ability.