Notch signaling controls the balance of ciliated and secretory cell fates in developing airways
Notch signaling controls the balance of ciliated and secretory cell fates in developing airways
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DOI：
10.1242/dev.034884
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发表时间：
2009-07-01
期刊：
影响因子：
4.6
通讯作者：
Cardoso, Wellington V.
中科院分区：
文献类型：
--
作者：
Tsao, Po-Nien;Vasconcelos, Michelle;Cardoso, Wellington V.
尽管有越来越多的证据表明Notch在发育中的肺中发挥作用，但仍不清楚Notch信号传导的破坏如何影响气道上皮中的肺祖细胞命运和分化事件。为了解决这个问题，我们使用Shh-Cre删除小鼠系和携带Pofut 1基因的floxed等位基因的小鼠有条件地灭活了内胚层中的Notch信号传导，Pofut 1基因编码Notch配体结合所必需的O-岩藻糖基转移酶。我们还采取了相同的条件性方法来表达Rbpjk，其编码经典Notch信号传导的转录效应子。引人注目的是，这些突变体表现出几乎相同的肺表型，其特征在于没有分泌性Clara细胞，没有细胞死亡的证据，并显示气道基本上由纤毛细胞填充，神经内分泌细胞增加。这种表型可以通过用γ-分泌酶抑制剂破坏Notch信号传导在培养的野生型肺中进一步复制。我们的数据表明，当近端祖细胞中发生纤毛或非纤毛细胞命运的承诺时，Notch起作用，使细胞中的纤毛程序沉默，这些细胞将继续扩增并分化为分泌细胞。这种机制可能是至关重要的，以确定在不同代的发展中的气道分化的细胞概况的平衡。它还可能与介导病理条件下发生的呼吸道上皮化生变化有关，如哮喘和慢性阻塞性肺病。
Although there is accumulated evidence of a role for Notch in the developing lung, it is still unclear how disruption of Notch signaling affects lung progenitor cell fate and differentiation events in the airway epithelium. To address this issue, we inactivated Notch signaling conditionally in the endoderm using a Shh-Cre deleter mouse line and mice carrying floxed alleles of the Pofut1 gene, which encodes an O-fucosyltransferase essential for Notch-ligand binding. We also took the same conditional approach to inactivate expression of Rbpjk, which encodes the transcriptional effector of canonical Notch signaling. Strikingly, these mutants showed an almost identical lung phenotype characterized by an absence of secretory Clara cells without evidence of cell death, and showed airways populated essentially by ciliated cells, with an increase in neuroendocrine cells. This phenotype could be further replicated in cultured wild-type lungs by disrupting Notch signaling with a gamma-secretase inhibitor. Our data suggest that Notch acts when commitment to a ciliated or non-ciliated cell fate occurs in proximal progenitors, silencing the ciliated program in the cells that will continue to expand and differentiate into secretory cells. This mechanism may be crucial to define the balance of differentiated cell profiles in different generations of the developing airways. It might also be relevant to mediate the metaplastic changes in the respiratory epithelium that occur in pathological conditions, such as asthma and chronic obstructive pulmonary disease.