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显著的影响，并有助于指导肺组织与人类干细胞的分化。胚胎肺的发育受一系列上皮-间质相互作用的调控。两种信号传导途径涉及来自前肠上皮的表达Nxk2.1的肺祖细胞的特化; FGF和Wnt 2/2b。在肺特化后，Wnt、FGF、Shh、TGF-β、BMP和RA通路之间的进一步相互作用调节肺芽生长、分化和形态发生。尽管最近取得了进展，但仍有一些关键的问题没有得到解答。首先，Wnt 2/2b上游的分子途径是不确定的。目前尚不清楚早期FGF和Wnt 2/2b是否在上位途径中起作用，并且它们的靶基因在很大程度上是未知的。最后，FGF/Wnt介导的肺特化和调节肺芽生长的途径之间的关系知之甚少。我们的初步数据支持这样的假设，即奇跳相关（Osr）锌指转录因子是上皮-间充质信号级联的关键组成部分，该级联将FGF的早期前肠模式与Wnt介导的肺特化和RA调节的肺芽生长连接成统一的分子途径。该提案采用创新的多系统方法，结合了非洲爪蟾胚胎学和小鼠遗传学的实验优势，有可能显着提高我们对早期肺发育的理解。目的1：探讨Osr 1/2转录因子调控非洲爪蟾肺发育的分子机制。目的2：验证Osr 1和Osr 2是小鼠肺发育所必需的假设。 公共卫生相关性：更好地了解肺的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。 人类干细胞组织。尽管最近取得了进展，但在我们对胚胎肺发育的理解中仍然存在一些关键的未回答的问题。该提案解决了其中的一些问题，并验证了Osr锌指转录因子调节信号级联反应的假设，该信号级联反应将早期前肠模式化、肺特化和肺芽生长连接到统一的分子途径中。

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.