Foxc1 is required for early stage telencephalic vascular development

Abstract

Background: The brain vascular system arises from the perineural vascular plexus (PNVP) which sprouts radially into the neuroepithelium and subsequently branches off laterally to form a secondary plexus in the subventricular zone (SVZ), the subventricular vascular plexus (SVP). The process of SVP formation remains to be fully elucidated. We investigated the role of Foxc1 in early stage vascular formation in the ventral telencephalon. Results: The Foxc1 loss of function mutant mouse, Foxc1 ch/ch , showed enlarged telencephalon and hemorrhaging in the ventral telencephalon by embryonic day 11.0. The mutant demonstrated blood vessel dilation and aggregation of endothelial cells in the SVZ after the invasion of endothelial cells through the radial path, which lead to failure of SVP formation. During this early stage of vascular development, Foxc1 was expressed in endothelial cells and pericytes, as well as in cranial mesenchyme surrounding the neural tube. Correspondingly, abnormal deposition pattern of basement membrane proteins around the vessels and increased strong Vegfr2 staining dots were found in the aggregation sites. Conclusions: These observations reveal an essential role for Foxc1 in the early stage of vascular formation in the telencephalon. Developmental Dynamics 244:703-711, 2015. V C 2015 Wiley Periodicals, Inc.

Cerebrovascular defects in Foxc1 mutants correlate with aberrant WNT and VEGF—A pathways downstream of retinoic acid from the meninges

“…1E-F) revealed significantly lower vessel density but significantly larger vessel diameter in Foxc1 mutants at E12.5. This is consistent with recent reports that defects in the Foxc1 mutant telencephalic vasculature appear as early as E10 in the ventral telencephalon (Prasitsak et al, 2015). …”

“…1E). This analysis is consistent with a recent report showing that, in contrast to the telencephalon, vascular density in the hindbrain was unchanged in global Foxc1 knockout mice (Prasitsak et al, 2015). Taken together, this data shows that conditional deletion of Foxc1 from endothelial cells or pericytes does not recapitulate the severe cerebrovascular defects observed in global Foxc1 mutants.…”

“…We show that vascular growth defects precede severe cerebral hemorrhage by several days, a finding consistent with published analysis of ventral vascular defects in an early Foxc1 mutant telencephalon (Prasitsak et al, 2015). Our observations bring up two important considerations.…”

“…Severe cerebral hemorrhage has been repeatedly reported in global Foxc1 knockout mice (Green, 1970; Gruneberg, 1943; Hecht et al, 2010; Siegenthaler et al, 2009) and, recently, vascular growth defects were described in early embryonic ventral telencephalon of Foxc1 mutants (Prasitsak et al, 2015). However, the role of Foxc1 in cerebrovascular development remains unclear.…”

Deletion of 6p25.3 Is Associated with Cerebrovascular Dolichoectasia: Report of 2 Cases

“…The FOXC1 gene, which is a transcription factor that contributes to the development and migration of neural crest cells and vascular development during embryogenesis, is often included in this deletion and has been cited as a driver of the phenotypic characteristics of these patients [4, 5]. Because of its neural crest cell disruption, this syndrome is associated with a myriad of symptoms ranging from dysmorphic facial features to congenital heart disease.…”