Foxp2 and Foxp1 cooperatively regulate lung and esophagus development
Foxp2 and Foxp1 cooperatively regulate lung and esophagus development
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DOI：
10.1242/dev.02846
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发表时间：
2007-05-15
期刊：
影响因子：
4.6
通讯作者：
Morrisey, Edward E.
中科院分区：
文献类型：
--
作者：
Shu, Weiguo;Lu, Min Min;Morrisey, Edward E.
肺的呼吸道通过分支形态发生的反复过程发展，这产生了出生后呼吸所需的复杂而广泛的表面积。叉头转录因子Foxp2和Foxp1在包括肺和肠在内的多种前肠组织中表达。在这篇报道中，我们发现Foxp2基因在小鼠体内的缺失会导致出生后肺泡形成缺陷，从而导致出生后死亡。通过体外和体内实验，我们证明T1pha是Foxp2和Foxp1的直接靶点，它是一种肺泡上皮1型细胞限制性基因，对肺发育和功能至关重要。值得注意的是，除Foxp2完全丢失外，单个Foxp1等位基因的丢失还会导致突变肺的形态缺陷严重程度增加，并导致所有Foxp2(-/-)；Foxp1(+/-)小鼠围产期丧失。在Foxp2(-/-)和Foxp1(+/-)突变体中，对肺发育至关重要的N-myc和Hop的表达受到影响。除了肺发育缺陷外，在Foxp2(-/-)；Foxp1(+/-)胚胎中，Foxp2(-/-)；Foxp1(+/-)胚胎的食道肌肉发育受到干扰，Foxp2和Foxp1共同表达的组织。这些数据表明Foxp2和Foxp1是肺和食道发育的关键调节因子，强调了这些转录因子在前肠组织发育中的必要性，并证明了Foxp1/2/4家族成员在它们共同表达的组织中的功能协同性。
The airways of the lung develop through a reiterative process of branching morphogenesis that gives rise to the intricate and extensive surface area required for postnatal respiration. The forkhead transcription factors Foxp2 and Foxp1 are expressed in multiple foregut-derived tissues including the lung and intestine. In this report, we show that loss of Foxp2 in mouse leads to defective postnatal lung alveolarization, contributing to postnatal lethality. Using in vitro and in vivo assays, we show that T1alpha, a lung alveolar epithelial type 1 cell-restricted gene crucial for lung development and function, is a direct target of Foxp2 and Foxp1. Remarkably, loss of a single Foxp1 allele in addition to complete loss of Foxp2 results in increased severity of morphological defects in mutant lungs and leads to perinatal loss of all Foxp2(-/-); Foxp1(+/-) mice. Expression of N-myc and Hop, crucial regulators of lung development, is compromised in Foxp2(-/-); Foxp1(+/-) mutants. In addition to the defects in lung development, esophageal muscle development is disrupted in Foxp2(-/-); Foxp1(+/-) embryos, a tissue where Foxp2 and Foxp1 are co-expressed. These data identify Foxp2 and Foxp1 as crucial regulators of lung and esophageal development, underscoring the necessity of these transcription factors in the development of anterior foregut-derived tissues and demonstrating functional cooperativity between members of the Foxp1/2/4 family in tissues where they are co- expressed.