Forkhead genes in mammalian cardiovascular development

哺乳动物心血管发育中的叉头基因

• 批准号: 6893311
• 负责人: BRIGID L.M. HOGAN
• 金额: $ 33.59万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6893311
• 关键词: angiogenesis; cell population study; congenital cardiovascular disorder; coronary vessels; developmental genetics; gene mutation; heart; laboratory mouse; mammalian embryology; neural crest; protein localization; transcription factor; vascular endothelium; angiogenesis; cell population study; congenital cardiovascular disorder; coronary vessels; developmental genetics; gene mutation; heart; laboratory mouse; mammalian embryology; neural crest; protein localization; transcription factor; vascular endothelium

The two closely related forkhead/winged helix transcription factors, Foxc1 (Mf1) and Foxc2 (Mfh1), are expressed in overlapping populations of cells contributing to endothelial cells of the heart and blood vessels and mesenchyme of the valves, outflow tract and aortic arches. We have shown that mice homozygous for null mutations in either Foxc1 or Foxc2 die pre- or perinatally with the same spectrum of cardiovascular defects, including interruption or coarctation of the aortic arch and ventricular septal defects. Most compound heterozygous mutant side with similar defects, leading to the central hypotheses that the two genes interact to regulate cardiovascular development, either through co-operative but non-identical functions, or strictly through dosage of the two gene products in the same. Using specific antibodies, we will determine the temporal and cellular localization of Foxc1 and Foxc2 protein in endothelial and neural crest mesenchyme during normal cardiovascular development (Aim 1), including coronary vessel development. The proposed hypothesis will be tested by analyzing the phenotype of more severe compound mutants and comparing these with single mutant phenotypes (Aim 2, 3). Finally, we will generate mutant mice in which Foxc1 is replaced with Foxc2 and vice versa to test if the two genes are interchangeable in vivo (Aim 2, 3). This aim will also generate conditional mutant alleles for deleting both genes in neural crest and epicardially-derived cells (Aim 2, 3).

两个密切相关的叉头/翼螺旋转录因子FOXC1（MF1）和FOXC2（MFH1）以重叠的细胞种群表达，这些细胞群体促进了心脏，血管，血管和瓣膜间质的内皮细胞，流出段和主动脉弓的间质。我们已经表明，在FOXC1或FOXC2中纯合子的小鼠前或围产期死亡，具有相同的心血管缺陷，包括主动脉弓和心室隔膜缺陷的中断或缩写。大多数具有相似缺陷的复合杂合突变侧，导致两个基因相互作用以通过合作但非相同的功能来调节心血管发育的中心假设，或者通过同一两个基因产物的剂量严格地通过剂量来调节心血管发育。使用特定的抗体，我们将在正常心血管发育期间（AIM 1）（包括冠状动脉血管发育）确定FOXC1和FOXC2蛋白在内皮和神经rest间质中的时间和细胞定位。提出的假设将通过分析更严重的化合物突变体的表型进行检验，并将其与单个突变体表型进行比较（AI​​M 2，3）。最后，我们将生成突变小鼠，其中FOXC1被FOXC2取代，反之亦然，以测试两个基因在体内是否可以互换（AIM 2，3）。该目标还将产生有条件的突变等位基因，以删除神经rest和心心衍生的细胞中的基因（AIM 2，3）。