Osr transcription factors regulate embryonic lung development

描述(由申请人提供)：更好地了解肺发育将对围产期健康产生广泛而重大的影响，并有助于指导肺组织与人类干细胞的区分。胚胎肺的发育受一系列上皮-间充质相互作用的调节。FGFs和Wnt2/2b这两条信号通路参与了Nxk2.1在前肠上皮细胞中的表达。在肺规范后，Wnt、Fgf、Shh、TGF-β、BMP和RA通路之间进一步串扰，调节肺芽的生长、分化和形态发生。尽管最近取得了进展，但仍有一些关键问题悬而未决。首先，WNT2/2b上游的分子途径尚未确定。目前尚不清楚早期的成纤维细胞生长因子和WNT2/2b是否通过上位性途径起作用，它们的靶基因在很大程度上也是未知的。最后，对成纤维细胞生长因子/Wnt介导的肺规范和调节肺芽生长的途径之间的关系还知之甚少。我们的初步数据支持这一假设，即奇数跳过相关(OSR)锌指转录因子是上皮-间充质信号级联的关键组成部分，将FGFs早期的前肠模式与Wnt介导的肺规范和RA调控的肺芽生长连接到一个统一的分子途径。这项建议使用了一种创新的多系统方法，结合了非洲爪哇胚胎学和小鼠遗传学的实验优势，有可能显著提高我们对早期肺发育的理解。目的1：确定Osr1/2转录因子调控非洲爪哇肺发育的分子途径的机制。目的2：验证OSR1和OSR2是小鼠肺发育所必需的假说。 公共卫生相关性：更好地了解肺发育将对围产期健康产生重大影响，并有助于指导肺的分化 来自人类干细胞的组织。尽管最近取得了进展，但在我们对胚胎肺发育的理解中仍有一些关键的问题尚未回答。这一建议解决了其中的一些问题，并检验了这样的假设，即OSR锌指转录因子调控一个信号级联，将早期前肠模式、肺规格和肺芽生长连接到一个统一的分子途径中。

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.