Fox Transcription Factors in Vascular Development

Fox 血管发育中的转录因子

• 批准号: 7737547
• 负责人: Tsutomu Kume
• 金额: $ 38.13万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7737547
• 关键词: Address; Adult; Arteries; Arteriovenous malformation; Blood; Blood Circulation; Blood Vessels; Cardinal vein; Cardiovascular Abnormalities; Cardiovascular system; Cell Differentiation process; Cells; Child; Congenital Abnormality; Development; Embryo; Endothelial Cells; Exhibits; Feedback; Foundations; Foxes; Gap Junctions; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Programming; Goals; Human; Inborn Genetic Diseases; Infant; Link; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic vessel; Maintenance; Mediating; Mesenchyme; Modeling; Molecular; Morphogenesis; Mus; Mutant Strains Mice; Neuropilin-1; Notch Signaling Pathway; Nuclear Receptors; Pathway interactions; Phenotype; Play; Population; Process; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Specific qualifier value; System; Testing; Therapeutic; Transcriptional Regulation; Vascular Diseases; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factors; Vascular System; Veins; Venous; apoAI regulatory protein-1; base; cell determination; embryonic stem cell; insight; mutant; notch protein; paracrine; progenitor; programs; promoter; public health relevance; receptor; transcription factor

DESCRIPTION (provided by applicant): The goal of this proposal is to define the mechanisms by which Foxc1 and Foxc2 regulate arterial specification and lymphatic vessel development. VEGF-A signaling activates the Notch-Delta like 4 (Dll4) pathway and induces expression of Neuropilin 1 (Nrp1), a co-receptor for VEGF-A, to promote the arterial program. In contrast, the COUP-TFII nuclear receptor suppresses the arterial cell fate by inhibiting the expression of Nrp1 and Notch signaling genes. After arteriovenous diversification, a subpopulation of the venous cells acquires a lymphatic cell fate by progressively expressing Sox18 and Prox1 and differentiates into lymphatic endothelial cells (LECs). Prox1/VEGF-R3+ LECs subsequently bud from the veins via paracrine VEGF-C signaling, leading to the formation of the lymphatic vasculature. We have recently demonstrated that Foxc1 and Foxc2 are essential for arterial specification by acting upstream of Notch signaling. Foxc proteins directly induce Notch signaling genes through the VEGF-A pathway. Moreover, compound Foxc1+/-; Foxc2-/- mutants exhibit a reduction in the number of Prox1+ LECs sprouting from the cardinal vein, and both Foxc genes are expressed in LECs and the surrounding mesenchyme. Our central hypothesis of this project is that Foxc1 and Foxc2 are essential for VEGF-mediated arterial cell determination and early lymphatic development. This hypothesis will be tested by: (1) determining molecular mechanisms by which Foxc1 and Foxc2 interact with the VEGF-A signaling pathway in arterial gene expression; (2) elucidating whether Foxc1 and Foxc2 regulate arterial cell identity in VEGF-R2+ endothelial progenitors; and (3) defining cell- autonomous and non-cell autonomous roles for Foxc1 and Foxc2 in lymphatic specification and the formation of the lymphatic vasculature. The mechanistic basis for a link between signaling pathways and transcriptional regulation in arterial, venous and lymphatic endothelial cells is still largely unknown. Completion of the proposed studies will define the fundamental mechanisms governing the formation of the vascular network during development. PUBLIC HEALTH RELEVANCE: Inherited disorders of the cardiovascular system are quite common in humans, but their causes and underlying developmental mechanisms are poorly understood. It is clear that mutant mice provide useful models to elucidate the molecular and cellular mechanisms of congenital cardiovascular anomalies, including arteriovenous malformations and abnormal lymphatic vessels. The proposed studies will significantly contribute to a better understanding of the causes of congenital defects associated with abnormal blood and lymphatic vessels in infants and children and gain insight into the cellular and molecular basis of human abnormalities.

描述（由申请人提供）：该提案的目标是定义 Foxc1 和 Foxc2 调节动脉规格和淋巴管发育的机制。 VEGF-A 信号传导激活 Notch-Delta 样 4 (Dll4) 通路并诱导 VEGF-A 共同受体 Neuropilin 1 (Nrp1) 的表达，以促进动脉程序。相比之下，COUP-TFII 核受体通过抑制 Nrp1 和 Notch 信号基因的表达来抑制动脉细胞的命运。动静脉多样化后，静脉细胞亚群通过逐渐表达 Sox18 和 Prox1 获得淋巴细胞命运，并分化为淋巴内皮细胞 (LEC)。 Prox1/VEGF-R3+ LEC 随后通过旁分泌 VEGF-C 信号从静脉中出芽，导致淋巴管系统的形成。我们最近证明 Foxc1 和 Foxc2 通过作用于 Notch 信号上游而对于动脉规范至关重要。 Foxc 蛋白通过 VEGF-A 途径直接诱导 Notch 信号基因。另外，化合物Foxc1+/-； Foxc2-/- 突变体表现出从主静脉萌发的 Prox1+ LEC 数量减少，并且两个 Foxc 基因均在 LEC 和周围的间充质中表达。我们这个项目的中心假设是 Foxc1 和 Foxc2 对于 VEGF 介导的动脉细胞测定和早期淋巴管发育至关重要。该假设将通过以下方式进行检验：（1）确定Foxc1和Foxc2与动脉基因表达中的VEGF-A信号通路相互作用的分子机制； (2) 阐明 Foxc1 和 Foxc2 是否调节 VEGF-R2+ 内皮祖细胞中的动脉细胞身份； (3) 定义 Foxc1 和 Foxc2 在淋巴管规范和淋巴管系统形成中的细胞自主和非细胞自主作用。动脉、静脉和淋巴内皮细胞信号通路和转录调节之间联系的机制基础仍然很大程度上未知。完成拟议的研究将确定发育过程中血管网络形成的基本机制。公共卫生相关性：遗传性心血管系统疾病在人类中相当常见，但对其原因和潜在的发育机制知之甚少。显然，突变小鼠提供了有用的模型来阐明先天性心血管异常（包括动静脉畸形和异常淋巴管）的分子和细胞机制。拟议的研究将极大地有助于更好地了解与婴儿和儿童血液和淋巴管异常相关的先天性缺陷的原因，并深入了解人类异常的细胞和分子基础。