VEGFR3 modulates brain microvessel branching in a mouse model of 22q11.2 deletion syndrome

Abstract

The loss of a single copy ofTBX1accounts for most of the clinical signs and symptoms of 22q11.2 deletion syndrome, a common genetic disorder that is characterized by multiple congenital anomalies and brain-related clinical problems, some of which likely have vascular origins.Tbx1mutant mice have brain vascular anomalies, thus making them a useful model to gain insights into the human disease. Here, we found that the main morphogenetic function of TBX1 in the mouse brain is to suppress vessel branching morphogenesis through regulation ofVegfr3. We demonstrate that inactivatingVegfr3in theTbx1expression domain on aTbx1mutant background enhances brain vessel branching and filopodia formation, whereas increasingVegfr3expression in this domain fully rescued these phenotypes. Similar results were obtained using an in vitro model of endothelial tubulogenesis. Overall, the results of this study provide genetic evidence thatVEGFR3is a regulator of early vessel branching and filopodia formation in the mouse brain and is a likely mediator of the brain vascular phenotype caused byTbx1loss of function.