A Gata6-Wnt pathway required for epithelial stem cell development and airway regeneration
A Gata6-Wnt pathway required for epithelial stem cell development and airway regeneration
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DOI：
10.1038/ng.157
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发表时间：
2008-07-01
期刊：
影响因子：
30.8
通讯作者：
Morrisey, Edward E.
中科院分区：
文献类型：
--
作者：
Zhang, Yuzhen;Goss, Ashley M.;Morrisey, Edward E.
已知包括肺在内的上皮器官通过激活内源性干细胞群体而具有再生能力，但调节干细胞扩增和再生的分子途径尚未得到充分理解。在这里，我们表明，Gata 6调节肺中支气管肺泡干细胞（BASCs）的时间外观和数量，其在Gata 6无效的肺上皮中的缺失导致BASCs的早熟外观和上皮分化的同时丧失。BASC的这种扩增是Gata 6缺失后肺上皮中典型Wnt信号传导显著增加的结果。非经典Wnt受体Fzd 2的表达在Gata 6突变体中下调，Fzd 2的增加或β-连环蛋白表达的减少部分地挽救了Gata 6突变体中的肺上皮缺陷。在肺上皮再生过程中，经典Wnt信号在含有BASC的小生境中被激活，并且Wnt信号的强制激活导致BASC数量的大量增加。此外，Gata 6是适当的肺上皮再生所必需的，出生后Gata 6的丢失导致BASC扩增增加和分化减少。总之，这些数据表明Gata 6调节的Wnt信号传导控制肺发育和再生所需的祖细胞扩增和上皮分化之间的平衡。
Epithelial organs, including the lung, are known to possess regenerative abilities through activation of endogenous stem cell populations, but the molecular pathways regulating stem cell expansion and regeneration are not well understood. Here we show that Gata6 regulates the temporal appearance and number of bronchioalveolar stem cells (BASCs) in the lung, its absence in Gata6-null lung epithelium leading to the precocious appearance of BASCs and concurrent loss in epithelial differentiation. This expansion of BASCs was the result of a pronounced increase in canonical Wnt signaling in lung epithelium upon loss of Gata6. Expression of the noncanonical Wnt receptor Fzd2 was downregulated in Gata6 mutants and increased Fzd2 or decreased beta-catenin expression rescued, in part, the lung epithelial defects in Gata6 mutants. During lung epithelial regeneration, canonical Wnt signaling was activated in the niche containing BASCs and forced activation of Wnt signaling led to a large increase in BASC numbers. Moreover, Gata6 was required for proper lung epithelial regeneration, and postnatal loss of Gata6 led to increased BASC expansion and decreased differentiation. Together, these data demonstrate that Gata6-regulated Wnt signaling controls the balance between progenitor expansion and epithelial differentiation required for both lung development and regeneration.