FGFR1-Frs2/3 signalling maintains sensory progenitors during inner ear hair cell formation.
FGFR1-Frs2/3 signalling maintains sensory progenitors during inner ear hair cell formation.
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DOI：
10.1371/journal.pgen.1004118
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发表时间：
2014-01
期刊：
影响因子：
4.5
通讯作者：
Ladher RK
中科院分区：
文献类型：
--
作者：
Ono K;Kita T;Sato S;O'Neill P;Mak SS;Paschaki M;Ito M;Gotoh N;Kawakami K;Sasai Y;Ladher RK
内耳机械感觉毛细胞传递声音和平衡信息。听觉毛细胞从内耳上皮中SOX2阳性的感觉块中长出，在发育过程中逐渐受到限制。这种限制取决于信号分子的作用。成纤维细胞生长因子(成纤维细胞生长因子)信号在感觉指定过程中很重要：FGFR1的减弱扰乱了耳蜗毛细胞的形成；然而，其潜在的机制仍不清楚。在这里，我们报告，在没有FGFR1信号的情况下，SOX2在感觉斑块中的表达不能维持。尽管前感觉域标志物p27Kip1、Hey2和Hes5表达下调，但祖细胞仍然可以退出细胞周期，形成非增殖区(ZNPC)，但形成感觉细胞的细胞数量减少。对一个不能与接头蛋白Frs2/3结合的突变的FGFR1等位基因的分析表明，Sox2的维持可以由MAP激酶调节。我们认为，通过激活MAP激酶，成纤维细胞生长因子信号对维持感觉前体细胞是必要的，并将前体作用于哺乳动物耳蜗感觉细胞的分化。我们大脑感知声音的能力取决于它在内耳的耳蜗处转化为电脉冲的能力。耳蜗有专门的细胞，称为内耳毛细胞，负责记录声音能量。环境影响、遗传障碍或仅仅是时间的流逝都会损害这些细胞，这种损害损害了我们的听力。如果我们能够了解这些细胞是如何发育的，我们或许能够利用这一知识来产生新的毛细胞。在这项研究中，我们解决了一个老问题：成纤维细胞生长因子家族的信号是如何控制毛细胞数量的？我们使用了成纤维细胞生长因子受体(FGFR1)的一个受体突变的小鼠，发现干细胞蛋白Sox2的表达没有保持。SOX2通常起到保持耳蜗内前体处于毛细胞前状态的作用。然而，在突变小鼠中，Sox2的表达是短暂的，降低了前体细胞决定毛细胞命运的能力。这些发现表明，通过调节成纤维细胞生长因子的活性，有可能扩大培养中的毛细胞前体细胞的数量，为替换受损的内耳毛细胞提供了一条途径。
Inner ear mechanosensory hair cells transduce sound and balance information. Auditory hair cells emerge from a Sox2-positive sensory patch in the inner ear epithelium, which is progressively restricted during development. This restriction depends on the action of signaling molecules. Fibroblast growth factor (FGF) signalling is important during sensory specification: attenuation of Fgfr1 disrupts cochlear hair cell formation; however, the underlying mechanisms remain unknown. Here we report that in the absence of FGFR1 signaling, the expression of Sox2 within the sensory patch is not maintained. Despite the down-regulation of the prosensory domain markers, p27Kip1, Hey2, and Hes5, progenitors can still exit the cell cycle to form the zone of non-proliferating cells (ZNPC), however the number of cells that form sensory cells is reduced. Analysis of a mutant Fgfr1 allele, unable to bind to the adaptor protein, Frs2/3, indicates that Sox2 maintenance can be regulated by MAP kinase. We suggest that FGF signaling, through the activation of MAP kinase, is necessary for the maintenance of sensory progenitors and commits precursors to sensory cell differentiation in the mammalian cochlea. The ability of our brain to perceive sound depends on its conversion into electrical impulses within the cochlea of the inner ear. The cochlea has dedicated specialized cells, called inner ear hair cells, which register sound energy. Environmental effects, genetic disorders or just the passage of time can damage these cells, and the damage impairs our ability to hear. If we could understand how these cells develop, we might be able to exploit this knowledge to generate new hair cells. In this study we address an old problem: how do signals from the fibroblast growth factor (FGF) family control hair cell number? We used mice in which one of the receptors for FGF (Fgfr1) is mutated and found that the expression of a stem cell protein, Sox2 is not maintained. Sox2 generally acts to keep precursors in the cochlea in a pre-hair cell state. However, in mutant mice Sox2 expression is transient, diminishing the ability of precursors to commit to a hair cell fate. These findings suggest that it may be possible to amplify the number of hair cell progenitors in culture by tuning FGF activity, providing a route to replace damaged inner ear hair cells.
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影响因子：
11.8
作者：
Ahmed, Mohi;Wong, Elaine Y. M.;Sun, Jianbo;Xu, Jinshu;Wang, Feng;Xu, Pin-Xian
通讯作者：
Xu, Pin-Xian
影响因子：
4.6
作者：
Hoch, RV;Soriano, P
通讯作者：
Soriano, P
影响因子：
4.6
作者：
Ishii, Yasuo;Weinberg, Kerry;Mikawa, Takashi
通讯作者：
Mikawa, Takashi
DOI：
10.1073/pnas.0808175105
发表时间：
2008-11-25
影响因子：
11.1
作者：
Dabdoub, Alain;Puligilla, Chandrakala;Kelley, Matthew W.
通讯作者：
Kelley, Matthew W.
影响因子：
4.5
作者：
Kiernan AE;Xu J;Gridley T
通讯作者：
Gridley T