Fox Transcription Factors in Vascular Development

描述(由申请人提供)：本提案的目标是确定Foxc1和FOXC2调节动脉规范和淋巴管发育的机制。血管内皮生长因子-A信号通路激活Notch-Delta like 4(DLL4)通路，并诱导血管内皮生长因子-A共同受体Neuropilin 1(Nrp1)的表达，从而促进动脉系统的发育。相反，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而获得淋巴细胞命运，并分化为淋巴管内皮细胞(LECs)。PROX1/VEGF-R3+LECs随后通过旁分泌的VEGF-C信号从静脉中萌发，导致淋巴管系统的形成。我们最近已经证明，Foxc1和FOXC2通过作用于Notch信号的上游，对动脉规范是必不可少的。FOXC蛋白通过血管内皮生长因子-A途径直接诱导Notch信号转导基因。此外，复合Foxc1+/-；FOXC2-/-突变体减少了Prox1+LECs从大静脉出芽的数量，并且两个Foxc基因都在LECs和周围的间质中表达。我们对这个项目的中心假设是，Foxc1和FOXC2对于血管内皮生长因子介导的动脉细胞决定和早期淋巴管发育是必不可少的。这一假说将通过以下几个方面得到验证：(1)确定Foxc1和FOXC2在动脉基因表达中与VEGF-A信号通路相互作用的分子机制；(2)阐明Foxc1和FOXC2是否调节血管内皮祖细胞中的动脉细胞特性；(3)确定Foxc1和FOXC2在淋巴管规范和淋巴管形成中的细胞自主和非细胞自主角色。动脉、静脉和淋巴管内皮细胞的信号通路和转录调控之间的联系的机制基础在很大程度上仍不清楚。拟议研究的完成将确定在发育过程中管理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，但其原因和潜在的发育机制尚不清楚。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的分子和细胞机制，包括动静脉畸形和异常淋巴管。拟议的研究将大大有助于更好地了解婴儿和儿童与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.