Cooperative functions of Hes/Hey genes in auditory hair cell and supporting cell development
Cooperative functions of Hes/Hey genes in auditory hair cell and supporting cell development
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DOI：
10.1016/j.ydbio.2011.01.038
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发表时间：
2009-12
影响因子：
2.9
通讯作者：
T. Tateya;I. Imayoshi;I. Tateya;J. Ito;R. Kageyama
中科院分区：
文献类型：
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作者：
T. Tateya;I. Imayoshi;I. Tateya;J. Ito;R. Kageyama
据报道，Notch介导的侧向抑制可以调节听觉毛细胞，并支持普通前体细胞的发育。虽然Notch效应基因Hes1、Hes5和Hey1在发育中的耳蜗组织中表达，但其中任何一种基因的失活都只会导致轻微的异常，提示它们的功能冗余。为了探讨Hes/Hey基因在耳蜗发育中的作用，我们研究了缺乏Hes1、Hes5和Hey1等位基因的复合杂合子或纯合子突变小鼠。我们发现，Hes/Hey基因剂量的减少会导致毛细胞形成的逐步增加。然而，如果Hes1、Hes5或Hey1至少有一个等位基因是完整的，毛细胞过多就会伴随着支持细胞的过度生产，这表明毛细胞的增加并不是以牺牲支持细胞为代价的，每个Hes/Hey基因都有诱导支持细胞的功能。相反，当Hes1、Hes5和Hey1的等位基因全部失活时，毛细胞的数量增加得更多，而支持细胞的数量与对照相比没有变化，这表明支持细胞的形成是通过它们的过剩生产和向毛细胞的命运转换来平衡的。突变体中细胞数量的增加似乎发生在前感觉域的形成之后，因为前感觉域的增殖状态和大小没有受到影响。因此，Hes1、Hes5和Hey1协同抑制毛细胞的形成，Hes1、Hes5或Hey1的一个等位基因足以支持细胞的产生，可能是通过侧向抑制感觉上皮来实现的。引人注目的是，尽管毛细胞过多，但Hes/嘿突变会导致细胞排列和极性紊乱，并导致听力损失。这些结果表明，Hes/Hey基因的剂量不仅是通过控制细胞增殖和侧向抑制而产生适当数量的毛细胞和支持细胞所必需的，而且还通过调节细胞的排列和极性来调节听力。
Notch-mediated lateral inhibition has been reported to regulate auditory hair cell and supporting cell development from common precursors. While the Notch effector genes Hes1, Hes5 and Hey1 are expressed in the developing cochlea, inactivation of either of them causes only mild abnormality, suggesting their functional redundancy. To explore the roles of Hes/Hey genes in cochlear development, we examined compound heterozygous or homozygous mutant mice that lacked Hes1, Hes5 and Hey1 alleles. We found that a reduction in Hes/Hey gene dosage led to graded increase of hair cell formation. However, if at least one allele of Hes1, Hes5 or Hey1 was intact, excessive hair cells were accompanied by overproduction of supporting cells, suggesting that the hair cell increase does not occur at the expense of supporting cells, and that each Hes/Hey gene functions to induce supporting cells. By contrast, when all alleles of Hes1, Hes5 and Hey1 were inactivated, the number of hair cells increased more drastically, whereas that of supporting cells was unchanged compared with control, suggesting that supporting cell formation was balanced by their overproduction and fate conversion into hair cells. The increase of the cell numbers seemed to occur after the prosensory domain formation in the mutants because the proliferation state and the size of the prosensory domain were not affected. Thus, Hes1, Hes5 and Hey1 cooperatively inhibit hair cell formation, and one allele of Hes1, Hes5 or Hey1 is sufficient for supporting cell production probably by lateral inhibition in the sensory epithelium. Strikingly, Hes/Hey mutations lead to disorganized cell alignment and polarity and to hearing loss despite hair cell overproduction. These results suggest that Hes/Hey gene dosage is essential not only for generation of appropriate numbers of hair cells and supporting cells by controlling cell proliferation and lateral inhibition but also for the hearing ability by regulating the cell alignment and polarity.