Fox Transcription Factors in Vascular Development

描述（由申请人提供）：本提案的目的是确定Foxc 1和Foxc 2调节动脉特化和淋巴管发育的机制。VEGF-A信号传导激活Notch-Delta样4（Dll 4）通路并诱导VEGF-A的共受体神经纤毛蛋白1（Nrp 1）的表达，以促进动脉程序。相反，COUP-TFII核受体通过抑制Nrp 1和Notch信号传导基因的表达来抑制动脉细胞的命运。在动静脉分化后，静脉细胞的亚群通过逐渐表达Sox 18和Prox 1获得淋巴细胞命运，并分化为淋巴管内皮细胞（LEC）。Prox 1/VEGF-R3+ LEC随后通过旁分泌VEGF-C信号传导从静脉出芽，导致淋巴管系统的形成。我们最近已经证明，Foxc 1和Foxc 2是必不可少的动脉规格的Notch信号上游。Foxc蛋白通过VEGF-A途径直接诱导Notch信号传导基因。此外，复合Foxc 1 +/-; Foxc 2-/-突变体表现出从主静脉出芽的Prox 1 + LEC的数量减少，并且两种Foxc基因在LEC和周围间充质中表达。我们这个项目的中心假设是Foxc 1和Foxc 2是VEGF介导的动脉细胞决定和早期淋巴发育所必需的。这一假设将通过以下方法进行检验：（1）确定Foxc 1和Foxc 2与动脉基因表达中VEGF-A信号通路相互作用的分子机制;（2）阐明Foxc 1和Foxc 2是否调节VEGF-R2+内皮祖细胞中动脉细胞的特性;和（3）确定Foxc 1和Foxc 2在淋巴特化和淋巴管系统形成中的细胞自主和非细胞自主作用。在动脉、静脉和淋巴管内皮细胞中，信号通路和转录调控之间联系的机制基础仍然很不清楚。完成拟议的研究将确定在发育过程中形成血管网的基本机制。公共卫生相关性：心血管系统的遗传性疾病在人类中相当常见，但其原因和潜在的发育机制知之甚少。很明显，突变小鼠提供了有用的模型，以阐明先天性心血管畸形，包括动静脉畸形和异常淋巴管的分子和细胞机制。拟议的研究将大大有助于更好地了解与婴儿和儿童异常血管和淋巴管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。

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.