Neurod1 suppresses hair cell differentiation in ear ganglia and regulates hair cell subtype development in the cochlea.
Neurod1 suppresses hair cell differentiation in ear ganglia and regulates hair cell subtype development in the cochlea.
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DOI：
10.1371/journal.pone.0011661
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发表时间：
2010-07-22
期刊：
影响因子：
3.7
通讯作者：
Fritzsch B
中科院分区：
文献类型：
--
作者：
Jahan I;Pan N;Kersigo J;Fritzsch B
至少有五个bHLH基因调节哺乳动物内耳中感觉神经元、毛细胞和支持细胞的细胞命运决定和分化。Atoh 1和Neurog 1的交叉调节导致Neurog 1缺失小鼠毛细胞的变化，尽管交叉调节的性质和机制尚未确定。Neurod 1受Neurog 1和Atoh 1共同调控，可能是这种交叉调节的介导者。我们使用Tg（Pax 2-Cre）有条件地删除内耳中的Neurod 1。我们的数据首次表明，Neurod 1的缺乏导致内耳感觉神经节内毛细胞的形成。三种细胞类型，神经嵴来源的雪旺细胞和间充质来源的成纤维细胞（均不表达Neurod 1）和内耳来源的神经元（表达Neurod 1）构成内耳神经节。最简单的解释是，Neurod 1抑制了感觉神经元发育为毛细胞的另一种命运。在没有Neurod 1的情况下，Atoh 1表达并将神经节内的细胞分化为毛细胞。我们通过证明Neurod 1也调节Corti器官中毛细胞亚型的分化来跟踪神经节中的这种效应。我们发现，在Neurod 1条件无效小鼠中，发育中的耳蜗顶端有几个基因的过早表达，外毛细胞转化为内毛细胞。我们的数据表明，Neurog 1对Atoh 1表达的长期交叉调节实际上可能在很大程度上是由Neurod 1介导的。我们认为，Neurod 1是由Neurog 1和Atoh 1调节，并提供了一个负反馈的基因。通过这种和其他反馈，Neurod 1抑制神经元的交替命运，以分化为毛细胞并调节毛细胞亚型。
At least five bHLH genes regulate cell fate determination and differentiation of sensory neurons, hair cells and supporting cells in the mammalian inner ear. Cross-regulation of Atoh1 and Neurog1 results in hair cell changes in Neurog1 null mice although the nature and mechanism of the cross-regulation has not yet been determined. Neurod1, regulated by both Neurog1 and Atoh1, could be the mediator of this cross-regulation. We used Tg(Pax2-Cre) to conditionally delete Neurod1 in the inner ear. Our data demonstrate for the first time that the absence of Neurod1 results in formation of hair cells within the inner ear sensory ganglia. Three cell types, neural crest derived Schwann cells and mesenchyme derived fibroblasts (neither expresses Neurod1) and inner ear derived neurons (which express Neurod1) constitute inner ear ganglia. The most parsimonious explanation is that Neurod1 suppresses the alternative fate of sensory neurons to develop as hair cells. In the absence of Neurod1, Atoh1 is expressed and differentiates cells within the ganglion into hair cells. We followed up on this effect in ganglia by demonstrating that Neurod1 also regulates differentiation of subtypes of hair cells in the organ of Corti. We show that in Neurod1 conditional null mice there is a premature expression of several genes in the apex of the developing cochlea and outer hair cells are transformed into inner hair cells. Our data suggest that the long noted cross-regulation of Atoh1 expression by Neurog1 might actually be mediated in large part by Neurod1. We suggest that Neurod1 is regulated by both Neurog1 and Atoh1 and provides a negative feedback for either gene. Through this and other feedback, Neurod1 suppresses alternate fates of neurons to differentiate as hair cells and regulates hair cell subtypes.
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影响因子：
2.5
作者：
Hayashi, Toshinori;Ray, Catherine A.;Younkins, Christa;Bermingham-McDonogh, Olivia
通讯作者：
Bermingham-McDonogh, Olivia
影响因子：
3.7
作者：
Fritzsch B;Dillard M;Lavado A;Harvey NL;Jahan I
通讯作者：
Jahan I
影响因子：
4.6
作者：
Alvarez, Y;Alonso, MT;Schimmang, T
通讯作者：
Schimmang, T
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.
DOI：
10.1002/neu.10098
发表时间：
2002-11-05
期刊：
JOURNAL OF NEUROBIOLOGY
影响因子：
--
作者：
Fritzsch, B;Beisel, KW;Reichardt, LF
通讯作者：
Reichardt, LF