Tbx1interacts genetically withVegfr3to regulate cardiac lymphangiogenesis in mice

The transcription factorTBX1is the major gene implicated in 22q11.2 deletion syndrome. The complex clinical phenotype includes vascular anomalies and a recent report presented new cases of primary lymphedema in 22q11.2DS patients. We have previously shown that Tbx1 activates Vegfr3 gene expression in lymphatic endothelial cells and that this activation is critical for lymphatic vessel development in prenatal mice and for their survival post-natally. Using loss-of-function genetics and transgenesis, we show a strong genetic interaction betweenTbx1andVegfr3in cardiac lymphangiogenesis that causes cardiac lymphatic vessel anomalies in compound heterozygotes. Intriguingly, different aspects of the cardiac lymphatic phenotype were regulated independently by the two genes.Tbx1Cre-activated Vegfr3 transgene expression was able to rescue the morphological abnormalities in the cardiac lymphatic vessels of compound heterozygotes, but it did not rescue the severe cardiac lymphatic vessel hypoplasia observed inTbx1homozygotes. Moreover, our study revealed a differential sensitivity between the ventral and dorsal cardiac lymphatic networks to the effects of alteredTbx1andVegfr3gene dosage. Overall, our study demonstrates that a fine dosage balance betweenTbx1andVegfr3is required to regulate the number and morphology of cardiac lymphatic vessels.