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

Abstract

The loss of a single copy of TBX1 accounts 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. Tbx1 mutant 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 of Vegfr3. We demonstrate that inactivating Vegfr3 in the Tbx1 expression domain on a Tbx1 mutant background enhances brain vessel branching and filopodia formation, whereas increasing Vegfr3 expression 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 that VEGFR3 is a regulator of early vessel branching and filopodia formation in the mouse brain and is a likely mediator of the brain vascular phenotype caused by Tbx1 loss of function.

Unique functional neuroimaging signatures of genetic versus clinical high risk for psychosis

“…A recent arterial spin labeling MRI study showed increased cerebral blood flow in 22qDel compared to controls (70). Additionally, animal models of 22qDel and studies of induced pluripotent stem cell-derived neurons from human 22qDel samples provide convergent evidence for neuronal mitochondrial disruption (71–74) and disrupted neurovascular development (75–78) caused by 22q11.2 CNVs. Neurovascular interactions are fundamental to the BOLD fMRI signal (79,80), and play a key role in neurodevelopmental processes such as cortical expansion (76,81,82), which appears to be strongly impacted in 22qDel given structural MRI findings of markedly reduced cortical surface area (83).…”

“…Additionally, animal models of 22qDel and studies of induced pluripotent stem cell-derived neurons from human 22qDel samples provide convergent evidence for neuronal mitochondrial disruption (71)(72)(73)(74) and disrupted neurovascular development (75)(76)(77)(78) caused by 22q11.2 CNVs.…”

Involvement of an Aberrant Vascular System in Neurodevelopmental, Neuropsychiatric, and Neuro-Degenerative Diseases

“…Tbx1, a transcription factor participating in organ development during prenatal life, reportedly plays a role in brain angiogenesis [ 23 ] ( Figure 1 ). Furthermore, Tbx1 heterozygous deficiency-mediated brain vascular anomalies such as brain vessel hyperplasia and increased filopodial density were recently demonstrated to be restored by Tbx1-Cre-induced activation of the vascular endothelial growth factor receptor 3 ( Vegfr3 ) transgene, suggesting that the brain vascular phenotype caused by Tbx1 loss of function is associated with the dysregulated expression of Vegfr3 [ 24 ]. Tbx1-deficient mice were shown to exhibit abnormalities in brain ECs, along with enhanced angiogenic sprouting, resulting in an expanded vascular network [ 25 ].…”