Osr1 functions downstream of Hedgehog pathway to regulate foregut development.
Osr1 functions downstream of Hedgehog pathway to regulate foregut development.
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DOI：
10.1016/j.ydbio.2017.05.005
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发表时间：
2017-07-01
影响因子：
2.7
通讯作者：
Zorn AM
中科院分区：
文献类型：
--
作者：
Han L;Xu J;Grigg E;Slack M;Chaturvedi P;Jiang R;Zorn AM
在早期胎儿发育期间，从前肠上皮分泌的旁分泌Hedgehog（HH）配体激活周围间充质中的Gli转录因子以协调呼吸系统、消化道和心血管网络的形成。尽管这一过程的中断可能导致毁灭性的先天性缺陷，但其潜在机制和下游靶点仍知之甚少。我们表明，锌指转录因子Osr1是一种新的HH目标，因为Osr1在前肠间充质中的表达依赖于HH信号传导，HH途径的效应子Gli3结合到Osr1启动子区域附近的保守基因组位点。小鼠生殖系Osr1突变体的分子分析揭示了Osr1在前肠发育过程中的多种功能。Osr1突变体在腹侧前肠中表现出较少的肺祖细胞。然后，原始肺芽的正确分支需要Osr，突变体表现出定位错误的肺叶。最后，Osr1对于包括肺动脉、食管和气管平滑肌以及气管软骨环在内的适当间充质分化是必不可少的。组织特异性条件敲除结合谱系追踪表明，Osr1是所需的细胞自主在前肠间充质。我们的结论是，Osr1是一个新的HH通路的下游目标，需要肺的规格，分支形态和前肠间充质分化。
During early fetal development, paracrine Hedgehog (HH) ligands secreted from the foregut epithelium activate Gli transcription factors in the surrounding mesenchyme to coordinate formation of the respiratory system, digestive track and the cardiovascular network. Although disruptions to this process can lead to devastating congenital defects, the underlying mechanisms and downstream targets, are poorly understood. We show that the zinc finger transcription factor Osr1 is a novel HH target as Osr1 expression in the foregut mesenchyme depends on HH signaling and the effector of HH pathway Gli3 binds to a conserved genomic loci near Osr1 promoter region. Molecular analysis of mouse germline Osr1 mutants reveals multiple functions of Osr1 during foregut development. Osr1 mutants exhibit fewer lung progenitors in the ventral foregut. Osr is then required for the proper branching of the primary lung buds, with mutants exhibiting miss-located lung lobes. Finally, Osr1 is essential for proper mesenchymal differentiation including pulmonary arteries, esophageal and tracheal smooth muscle as well as tracheal cartilage rings. Tissue specific conditional knockouts in combination with lineage tracing indicate that Osr1 is required cell autonomously in the foregut mesenchyme. We conclude that Osr1 is a novel downstream target of HH pathway, required for lung specification, branching morphogenesis and foregut mesenchymal differentiation.
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