Eya1 controls cell polarity, spindle orientation, cell fate and Notch signaling in distal embryonic lung epithelium (Retracted article. See vol. 144, pg. 3849, 2017)
Eya1 controls cell polarity, spindle orientation, cell fate and Notch signaling in distal embryonic lung epithelium (Retracted article. See vol. 144, pg. 3849, 2017)
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DOI：
10.1242/dev.058479
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发表时间：
2011-04-01
期刊：
影响因子：
4.6
通讯作者：
Warburton, David
中科院分区：
文献类型：
--
作者：
El-Hashash, Ahmed H. K.;Turcatel, Gianluca;Warburton, David
细胞极性、有丝分裂纺锤体取向和不对称分裂在上皮细胞的自我更新/分化中起着至关重要的作用，但在胚胎肺远端上皮中，对这些过程和控制它们的分子程序知之甚少。在此，我们提供了第一个证据，证明胚胎肺远端上皮是极化的，具有典型的垂直细胞分裂。与这些发现一致，纺锤体取向调节蛋白Insc、LGN （Gpsm2）和NuMA以及细胞命运决定因子Numb不对称地定位于胚胎肺远端上皮。在体外干扰这些蛋白的功能会使纺锤体取向随机化并改变细胞命运。我们进一步发现Eya1蛋白调节细胞极性、纺锤体取向和Numb的定位，从而抑制Notch信号。因此，Eya1可能通过控制aPKC zeta磷酸化，促进有丝分裂远端肺上皮的垂直分裂和麻木不对称分离。因此，在体内或体外干扰Eya1功能后，上皮细胞极性和有丝分裂纺锤体取向都有缺陷。此外，在Eya1（-/-）肺中，有丝分裂上皮细胞中的垂直分裂无法维持，Numb被分离到两个子细胞中，导致Notch信号失活。由于Notch信号通路以牺牲分化的细胞表型为代价促进祖细胞的身份，我们测试了Notch的遗传激活是否可以挽救Eya1（-/-）肺表型，其特征是上皮祖细胞的丧失，上皮分化增加，但分支减少。事实上，基因激活Notch部分地挽救了Eya1（-/-）肺上皮缺陷。这些发现揭示了Eya1作为远端胚胎肺上皮复杂行为的关键调节因子的新功能。
Cell polarity, mitotic spindle orientation and asymmetric division play a crucial role in the self-renewal/differentiation of epithelial cells, yet little is known about these processes and the molecular programs that control them in embryonic lung distal epithelium. Herein, we provide the first evidence that embryonic lung distal epithelium is polarized with characteristic perpendicular cell divisions. Consistent with these findings, spindle orientation-regulatory proteins Insc, LGN (Gpsm2) and NuMA, and the cell fate determinant Numb are asymmetrically localized in embryonic lung distal epithelium. Interfering with the function of these proteins in vitro randomizes spindle orientation and changes cell fate. We further show that Eya1 protein regulates cell polarity, spindle orientation and the localization of Numb, which inhibits Notch signaling. Hence, Eya1 promotes both perpendicular division as well as Numb asymmetric segregation to one daughter in mitotic distal lung epithelium, probably by controlling aPKC zeta phosphorylation. Thus, epithelial cell polarity and mitotic spindle orientation are defective after interfering with Eya1 function in vivo or in vitro. In addition, in Eya1(-/-) lungs, perpendicular division is not maintained and Numb is segregated to both daughter cells in mitotic epithelial cells, leading to inactivation of Notch signaling. As Notch signaling promotes progenitor cell identity at the expense of differentiated cell phenotypes, we test whether genetic activation of Notch could rescue the Eya1(-/-) lung phenotype, which is characterized by loss of epithelial progenitors, increased epithelial differentiation but reduced branching. Indeed, genetic activation of Notch partially rescues Eya1(-/-) lung epithelial defects. These findings uncover novel functions for Eya1 as a crucial regulator of the complex behavior of distal embryonic lung epithelium.