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.
The cranial base is a structure mainly formed through endochondral ossification and integrated into the craniofacial complex, which acts as an underlying platform for the developing brain. Foxc1 is an indispensable regulator during intramembranous and endochondral ossification. In this study, we found that the spontaneous loss of Foxc1 function in a mouse (congenital hydrocephalous), Foxc1 , demonstrated the anterior cranial base defects, including unossified presphenoid and lack of middle part of the basisphenoid bone. Hypoplastic presphenoid primordial cartilage (basal portion of the trabecular cartilage [bTB]) and a lack of the middle part of basisphenoid primordial cartilage (the hypophyseal cartilage) were consistently observed at earlier developmental stage. Foxc1 was expressed robustly and ubiquitously in undifferentiated mesenchyme of the cranial base-forming area in E11.0 wild-type fetuses. Once chondrogenesis commenced, the expression was downregulated and later limited to the perichondrium. Detection of transcripts of Collagen type2 A1 (Col2a1) revealed that both bTB and the anterior part of the hypophyseal cartilage developing anterior to the persistent epithelial stalk of the anterior lobe of the pituitary gland were suppressed in the Foxc1 . Proliferation activity of chondrocyte precursor cells was higher in the Foxc1 . Loss of Foxc1 function only in the neural crest cell lineage (Wnt1-cre;Foxc1 ) showed ossification of the posterior part of the hypophyseal cartilage derived from the mesoderm. These findings suggest that Foxc1 is an important regulator to further chondrogenesis and initiate the ossification of the presphenoid and basisphenoid bones.
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