Cerebrovascular defects in Foxc1 mutants correlate with aberrant WNT and VEGF-A pathways downstream of retinoic acid from the meninges.
Growth and maturation of the cerebrovasculature is a vital event in neocortical development however mechanisms that control cerebrovascular development remain poorly understood. Mutations in or deletions that include the FOXC1 gene are associated with congenital cerebrovascular anomalies and increased stroke risk in patients. Foxc1 mutant mice display severe cerebrovascular hemorrhage at late gestational ages. While these data demonstrate Foxc1 is required for cerebrovascular development, its broad expression in the brain vasculature combined with Foxc1 mutant's complex developmental defects have made it difficult to pinpoint its function(s). Using global and conditional Foxc1 mutants, we find 1) significant cerebrovascular growth defects precede cerebral hemorrhage and 2) expression of Foxc1 in neural crest-derived meninges and brain pericytes, though not endothelial cells, is required for normal cerebrovascular development. We provide evidence that reduced levels of meninges-derived retinoic acid (RA), caused by defects in meninges formation in Foxc1 mutants, is a major contributing factor to the cerebrovascular growth defects in Foxc1 mutants. We provide data that suggests that meninges-derived RA ensures adequate growth of the neocortical vasculature via regulating expression of WNT pathway proteins and neural progenitor derived-VEGF-A. Our findings offer the first evidence for a role of the meninges in brain vascular development and provide new insight into potential causes of cerebrovascular defects in patients with FOXC1 mutations.
Department of Pediatrics, Section of Developmental Biology, University of Colorado, School of Medicine Aurora, CO 80045, USA.
Swati
S
Mishra
Department of Neurology, Programs in Neuroscience and Developmental Biology, Institute for Regenerative Medicine, UC San Francisco, San Francisco, CA 94158, USA.
Youngshik
Y
Choe
Department of Neurology, Programs in Neuroscience and Developmental Biology, Institute for Regenerative Medicine, UC San Francisco, San Francisco, CA 94158, USA.
Samuel J
SJ
Pleasure
Department of Pediatrics, Section of Developmental Biology, University of Colorado, School of Medicine Aurora, CO 80045, USA. Electronic address: julie.siegenthaler@ucdenver.edu.
Julie A
JA
Siegenthaler
D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D001921:Brain / Q000002:abnormalities* / Q000098:blood supply / Q000473:pathology; D002478:Cells, Cultured; D002543:Cerebral Hemorrhage / Q000473:pathology; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000187:drug effects / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D019426:Integrases / Q000378:metabolism; D008578:Meninges / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics*; D019579:Neocortex / Q000098:blood supply / Q000196:embryology / Q000473:pathology; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism
D051858:Forkhead Transcription Factors; C112890:Foxc1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D051153:Wnt Proteins; D014212:Tretinoin; C045073:Cre recombinase; D019426:Integrases; D001616:beta-Galactosidase
Cerebrovascular development; Endothelial cell; Foxc1; Meninges; VEGF; WNT
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