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。VEGF-A信号激活Notch-Delta样4 （Dll4）通路，诱导VEGF-A共受体Neuropilin 1 （Nrp1）的表达，从而促进动脉程序。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。在动静脉分化后，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（LECs）。Prox1/VEGF-R3+ LECs随后通过旁分泌VEGF-C信号从静脉中萌发，导致淋巴血管的形成。我们最近证明Foxc1和Foxc2通过作用于Notch信号的上游对动脉规范至关重要。Foxc蛋白通过VEGF-A途径直接诱导Notch信号基因。化合物Foxc1+/-；Foxc2-/-突变体表现出从主静脉萌发的Prox1+ LECs数量减少，Foxc基因在LECs和周围的间质中表达。我们的中心假设是Foxc1和Foxc2对vegf介导的动脉细胞测定和早期淋巴发育至关重要。这一假设将通过以下方式得到验证：(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VEGF-R2+内皮祖细胞的动脉细胞身份；(3)确定Foxc1和Foxc2在淋巴规范和淋巴血管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中信号通路和转录调控之间联系的机制基础仍然很大程度上是未知的。拟议研究的完成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：心血管系统的遗传性疾病在人类中很常见，但其病因和潜在的发育机制尚不清楚。很明显，突变小鼠为阐明先天性心血管异常（包括动静脉畸形和淋巴管异常）的分子和细胞机制提供了有用的模型。所提出的研究将显著有助于更好地了解婴儿和儿童与异常血液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.