Osr transcription factors regulate embryonic lung development

描述（由申请人提供）：更好地了解肺部发育将对围产期健康产生广泛而重要的影响，并促进指导肺组织从人类干细胞分化的努力。胚胎肺的发育受一系列上皮-间质相互作用的调控。两种信号通路涉及前肠上皮中表达nxk2.1的肺祖细胞的特异性；FGFs和Wnt2/2b。肺规范后，Wnt、FGF、Shh、TGF-¿、BMP和RA通路之间进一步串扰，调控肺芽的生长、分化和形态发生。尽管最近取得了进展，但仍有一些关键的未解之谜。首先，Wnt2/2b上游的分子通路尚不明确。目前尚不清楚早期FGF和Wnt2/2b是否在上位性途径中起作用，它们的靶基因在很大程度上是未知的。最后，FGF/ wnt介导的肺规范与肺芽生长调节途径之间的关系尚不清楚。我们的初步数据支持这样的假设，即Odd跳过相关（Osr）锌指转录因子是上皮-间质信号级联的关键组成部分，该级联将FGFs的早期前肠模式与wnt介导的肺规范和ra调节的肺芽生长连接到统一的分子途径中。该建议采用了一种创新的多系统方法，结合了爪蟾胚胎学和小鼠遗传学的实验优势，有可能显著促进我们对早期肺发育的理解。目的1：确定Osr1/2转录因子调控爪蟾肺发育分子通路的机制。目的2：验证Osr1和Osr2是小鼠肺发育所必需的假设。

DESCRIPTION (provided by applicant): A better understanding of lung development will have a broad and significant impact on perinatal health and facilitate efforts to direct the differentiaion of pulmonary tissue from human stem cells. Embryonic lung development is regulated by a series of epithelial-mesenchymal interactions. Two signaling pathways have been implicated in the specification of Nxk2.1-expressing lung progenitors from the foregut epithelium; FGFs and Wnt2/2b. After pulmonary specification further crosstalk between Wnt, FGF, Shh, TGF-¿, BMP and RA pathways regulate lung bud growth, differentiation and morphogenesis. Despite recent progress a number of critical unanswered questions remain. First, the molecular pathways upstream of Wnt2/2b are undefined. It is unclear if early FGF and Wnt2/2b act in an epistatic pathway and their target genes are largely unknown. Finally the relationship between FGF/Wnt-mediated lung specification and the pathways regulating lung bud growth are poorly understood. Our preliminary data support the hypothesis that the Odd skipped related (Osr) zinc finger transcription factors are key components of an epithelial-mesenchymal signaling cascade linking early foregut patterning by FGFs to Wnt-mediated pulmonary specification and RA-regulated lung bud growth into a unified molecular pathway. This proposal, which uses an innovative multi-system approach combining the experimental advantages of Xenopus embryology and mouse genetics, has the potential to significantly advance our understanding of early lung development. Aim 1: Determine the mechanisms by which Osr1/2 transcription factors regulate the molecular pathway controlling Xenopus lung development. Aim 2: Test the hypothesis that Osr1 and Osr2 are required for lung development in mice. PUBLIC HEALTH RELEVANCE: A better understanding of lung development will have a significant impact on perinatal health and facilitate efforts to direct the differentiation of lung tissue from human stem cells. Despite recent progress there are a number of critical unanswered questions that remain in our understanding of embryonic lung development. This proposal addresses some of these and tests the hypothesis that Osr zinc finger transcription factors regulate a signaling cascade linking early foregut patterning, pulmonary specification and lung bud growth into a unified molecular pathway.