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.
Stroke is a significant case of long-term disability and death and can result from congenital vascular defects that occur during fetal development. The research in this proposal seeks to significantly expand our understanding of what controls the formation of the cerebral vasculature. Understanding how the cerebral vasculature forms will not only shed light on the etiology of congenital vascular malformations but also provide insight into the developmental angiogenic pathways that are likely reactivated during stroke recovery.
|Mishra, Swati; Choe, Youngshik; Pleasure, Samuel J et al. (2016) Cerebrovascular defects in Foxc1 mutants correlate with aberrant WNT and VEGF-A pathways downstream of retinoic acid from the meninges. Dev Biol 420:148-165|
|Kelly, Kathleen K; MacPherson, Amber M; Grewal, Himmat et al. (2016) Col1a1+ perivascular cells in the brain are a source of retinoic acid following stroke. BMC Neurosci 17:49|
|Bonney, Stephanie; Harrison-Uy, Susan; Mishra, Swati et al. (2016) Diverse Functions of Retinoic Acid in Brain Vascular Development. J Neurosci 36:7786-801|
|Arnold, Thomas D; Niaudet, Colin; Pang, Mei-Fong et al. (2014) Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking Î±VÎ²8-TGFÎ² signaling in the brain. Development 141:4489-99|
|Siegenthaler, Julie A; Choe, Youngshik; Patterson, Katelin P et al. (2013) Foxc1 is required by pericytes during fetal brain angiogenesis. Biol Open 2:647-59|
|Siegenthaler, Julie A; Sohet, Fabien; Daneman, Richard (2013) 'Sealing off the CNS': cellular and molecular regulation of blood-brain barriergenesis. Curr Opin Neurobiol 23:1057-64|
|Choe, Youngshik; Siegenthaler, Julie A; Pleasure, Samuel J (2012) A cascade of morphogenic signaling initiated by the meninges controls corpus callosum formation. Neuron 73:698-712|