Activated notch causes deafness by promoting a supporting cell phenotype in developing auditory hair cells.
Activated notch causes deafness by promoting a supporting cell phenotype in developing auditory hair cells.
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DOI：
10.1371/journal.pone.0108160
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kiernan AE
中科院分区：
文献类型：
--
作者：
Savoy-Burke G;Gilels FA;Pan W;Pratt D;Que J;Gan L;White PM;Kiernan AE
目的：确定在内耳感觉细胞分化过程中，激活的Notch能否促进支持细胞的命运。一种激活形式的Notch1受体(NICD)使用Gfi1-Cre小鼠等位基因在早期分化的毛细胞中表达。为了确定激活的Notch对毛细胞发育的影响，在5周时通过测量听性脑干反应(ABR)和失真产物耳声发射(DPOAEs)来评估Gfi1-NICD动物及其仔鼠对照组的听力。在出生后第6、11和20天，使用毛细胞以及支持细胞/祖细胞的组织学和分子标记，评估表达NICD的毛细胞的分化情况。我们还研究了Notch的作用是否由SOX2介导，SOX2是一种在支持细胞中表达的基因，也是Notch可能的下游靶点，通过将SOX2的诱导形式与Gfi1-CRE杂交。在发育中的听觉毛细胞中，Notch1的激活会导致深度耳聋。表达NICD的毛细胞关闭了许多毛细胞标记，失去了它们特有的形态。相反，表达NICD的毛细胞采用类似于支持细胞的形态，并上调一些支持细胞标记。这些作用似乎不是由SOX2介导的，因为尽管SOX2的表达导致了一些听力障碍，但表达SOX2的毛细胞既不下调毛细胞标志物，也不表现出支持细胞样表型。我们的数据显示，Notch信号抑制毛细胞分化，促进支持细胞样表型，这些作用不太可能由SOX2介导。
To determine whether activated Notch can promote a supporting cell fate during sensory cell differentiation in the inner ear. An activated form of the Notch1 receptor (NICD) was expressed in early differentiating hair cells using a Gfi1-Cre mouse allele. To determine the effects of activated Notch on developing hair cells, Gfi1-NICD animals and their littermate controls were assessed at 5 weeks for hearing by measuring auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). The differentiation of NICD-expressing hair cells was assessed at postnatal day (P) 6, 11 and 20, using histological and molecular markers for hair cells, as well as supporting cells/progenitor cells. We also examined whether the effects of Notch were mediated by SOX2, a gene expressed in supporting cells and a likely downstream target of Notch, by crossing an inducible form of SOX2 to the Gfi1-Cre. Activation of Notch1 in developing auditory hair cells causes profound deafness. The NICD-expressing hair cells switch off a number of hair cell markers and lose their characteristic morphology. Instead, NICD-expressing hair cells adopt a morphology resembling supporting cells and upregulate a number of supporting cell markers. These effects do not appear to be mediated by SOX2, because although expression of SOX2 caused some hearing impairment, the SOX2-expressing hair cells did not downregulate hair cell markers nor exhibit a supporting cell-like phenotype. Our data show that Notch signaling inhibits hair cell differentiation and promotes a supporting cell-like phenotype, and that these effects are unlikely to be mediated by SOX2.
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DOI：
10.1073/pnas.1003089107
发表时间：
2010-09-07
影响因子：
11.1
作者：
Pan, Wei;Jin, Ying;Kiernan, Amy E.
通讯作者：
Kiernan, Amy E.
DOI：
10.4171/rmi/104
发表时间：
1991-01-01
期刊：
CIBA FOUNDATION SYMPOSIA
影响因子：
--
作者：
LEWIS, J
通讯作者：
LEWIS, J
影响因子：
3.7
作者：
Liu Z;Owen T;Fang J;Zuo J
通讯作者：
Zuo J
影响因子：
3.7
作者：
Freeman SD;Daudet N
通讯作者：
Daudet N
影响因子：
34.7
作者：
Goldman, Daniel
通讯作者：
Goldman, Daniel