Fetal Lung Development:Role of Wnt5a Signaling

胎儿肺发育：Wnt5a 信号传导的作用

• 批准号: 7430341
• 负责人: CHANGGONG LI
• 金额: $ 30.91万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-12 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7430341
• 关键词: Affect; Alveolar; Biological; Birth; Body Size; Cell Communication; Cell Proliferation; Cell physiology; Cells; Cessation of life; Communication; Data; Development; Drosophila genus; Embryonic Development; Epithelial; Family; Fetal Lung; Gene Targeting; Genes; Glycoproteins; Homologous Gene; Lung; Lung diseases; Mediating; Mediator of activation protein; Mesenchymal; Molecular; Morphogenesis; Mus; Mutant Strains Mice; Numbers; Organ; Organogenesis; Pathway interactions; Perinatal; Phenotype; Protein Family; Regulation; Respiratory Insufficiency; Role; SHH gene; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Specificity; Testing; Transgenic Mice; WNT Signaling Pathway; base; beta catenin; cysteine rich protein; loss of function; lung development; member; receptor; response; size

DESCRIPTION (provided by applicant): Developmental signaling through the wingless/frizzled pathway is an evolutionarily highly conserved mechanism that figures importantly in morphogenesis of many organs. Little information is available regarding the role of this pathway and its mediators in lung morphogenesis. We have examined the consequences of functional deletion of Wnt5a on lung development in mouse. The mutant mice have multiple developmental abnormalities and die shortly after birth with respiratory insufficiency. Preliminary data suggest that absence of Wnt5a results in increased cellular proliferation, enhanced pseudoglandular branching morphogenesis, increased overall lung/body size ration, but inhibits the maturation of the alveolar septa (thickened interstitium). Also, expression of Shh, Ptc, Fgfl0 and Bmp4 are all increased in Wnt5a(-/-) lungs. We propose that: Hypothesis: WNT5a affects fetal lung development through interactions with the SHH pathway. Three Specific Aims are proposed to test the latter hypothesis. Specific Aim 1. To further investigate the role Wnt5a by generating & characterizing SpC: Wnt5a transgenic mice. Specific Aim 2. To determine the interactions of SHH & WNT signaling in lung development. Specific Aim 3. To determine receptor specificity and intracellular mediators of WNT5a pathway in the lung. Characterization of the precise role of Wnt5a will contribute to our understanding of cell-to-cell communication and lung development. This information will be of utility in understanding the molecular mechanisms of congenital and induced lung disease.

描述(申请人提供)：通过无翅/卷曲途径的发育信号是一种进化上高度保守的机制，在许多器官的形态发生中扮演着重要的角色。关于这一途径及其介体在肺形态发生中的作用，目前知之甚少。我们研究了Wnt5a功能缺失对小鼠肺发育的影响。突变小鼠有多种发育异常，出生后不久就死于呼吸功能不全。初步数据表明，WNT5a的缺失导致细胞增殖增加，伪腺分支形态发生增强，整体肺/体大小比增加，但抑制了肺泡间隔(增厚的间质)的成熟。Wnt5a(-/-)肺组织中Shh、PTC、Fgfl0和Bmp4的表达均增加。我们建议： 假设：Wnt5A通过与SHH途径相互作用影响胎儿肺发育。 为了检验后一种假设，本文提出了三个具体目标。 具体目的1.通过建立和鉴定SPC：Wnt5A转基因小鼠，进一步研究Wnt5a的作用。 具体目的2.探讨SHH和WNT信号在肺发育中的相互作用。具体目的3.确定肺组织中Wnt5A途径的受体特异性和细胞内介质。 Wnt5a的确切作用将有助于我们理解细胞间的通讯和肺的发育。这些信息将有助于理解先天性和诱发性肺部疾病的分子机制。

项目成果

Ror2 modulates the canonical Wnt signaling in lung epithelial cells through cooperation with Fzd2.

• DOI: 10.1186/1471-2199-9-11
• 发表时间: 2008-01-23
• 期刊: BMC molecular biology
• 作者: Li C;Chen H;Hu L;Xing Y;Sasaki T;Villosis MF;Li J;Nishita M;Minami Y;Minoo P
• 通讯作者: Minoo P