Forebrain angiogenesis in Foxc1 mutant mice

大脑需要不间断的血液供应来生长和发挥功能，以至于中风或受伤造成的血流中断往往会导致永久性残疾。将血液运送到神经组织和从神经组织运送血液的血管网络在发育过程中形成，并在个体的整个生命周期中维持。该系统的生长和稳定性取决于血管与周围环境之间的重要通信，周围环境包括神经嵴衍生的细胞，如周细胞和脑膜成纤维细胞以及大脑本身。该提案中的实验利用Foxc 1突变小鼠，这些小鼠在血管和大脑发育方面都有缺陷，以进一步了解脑血管系统如何形成。这种方法是独特的，因为Foxc 1在脑内皮细胞（EC）功能中没有细胞自主作用。相反，血管发育的缺陷可能源于血管附近组织和细胞发出的重要发育线索的丢失。这项资助的一个目标是确定在Fox 1突变小鼠中，脑膜缺失和新皮层发育缺陷如何不同地导致血管畸形。我们将重点关注Wnt和VEGF等神经源性血管生成信号的潜在破坏如何改变神经周围和新皮质血管丛的血管发育。Foxc 1由脑周细胞表达，但其在这种细胞类型中的功能尚不清楚。对周细胞条件性Foxc 1突变小鼠的分析表明，Foxc 1在周细胞-内皮相互作用中起着不可或缺的作用，特别是在调节两种细胞类型的细胞增殖中。我们建议使用遗传分析和体外实验来确定Foxc 1下游的周细胞衍生因子，并确定它们如何调节神经血管系统中的细胞增殖。

The brain requires an uninterrupted supply of blood to grow and function so much so that interruption of blood flow caused by stroke or injury often causes permanent disability. The network of vessels that carry blood to and from neural tissue are formed during development and are maintained throughout the lifetime of an individual. The growth and stability of this system depends upon important communication between the blood vessel and the surrounding milieu, which includes neural crest-derived cells like pericytes and meningeal fibroblasts and the brain itself. Experiments in this proposal utilize Foxc1 mutant mice, which have defects in both vascular and brain development, to gain further insight into how the brain vasculature forms. This approach is unique because Foxc1 does not have a cell autonomous role in brain endothelial cell (EC) function. Rather, the defects in vascular development likely stem from the loss of important developmental cues that emanate from tissues and cells adjacent to the blood vessels. One goal of this grant is to determine how absence of the meninges and defects in neocortical development differentially contribute to vascular malformations in Fox1 mutant mice. We will be focusing on how potential disruption of neural derived angiogenic cues like Wnt and VEGF alters vascular development in the perineural and neocortical vascular plexuses. Foxc1 is expressed by brain pericytes but its function in this cell-type is unknown. Analysis of a pericyte conditional Foxc1 mutant mice suggest that Foxc1 plays in integral role in pericyteendothelial interactions, specifically in regulating cell proliferation of both cell types. We propose to use genetic profiling and in vitro experiments in to identify pericyte derived factors downstream of Foxc1 and determine how they may regulate cell proliferation in the neural vasculature.