A dual role forTbx1in cardiac lymphangiogenesis through genetic interaction withVegfr3

[摘要] The transcription factorTBX1is the major gene implicated in 22q11.2 deletion syndrome (22q11.2DS). 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 is required for systemic lymphatic vessel development in prenatal mice and it is critical for their survival postnatally. Using loss-of-function genetics and transgenesis in the mouse, we show here a strong genetic interaction betweenTbx1andVegfr3in cardiac lymphangiogenesis. Intriguingly, we found that different aspects of the cardiac lymphatic phenotype inTbx1-Vegfr3compound heterozygotes were regulated independently by the two genes, withTbx1primarily regulating vessel numbers andVegfr3vessel morphology. Consistent with this observation,Tbx1(Cre)-activated expression of aVegfr3transgene rescued partially the cardiac lymphatic abnormalities in compound heterozygotes. Through time-controlled genetic experiments, we show thatTbx1is activated and required in cardiac lymphatic endothelial cell (LEC) progenitors between E10.5 and E11.5. Furthermore, we found that it is also required later in development for the growth of the cardiac lymphatics. Finally, our study revealed a differential sensitivity between ventral and dorsal cardiac lymphatics to the effects of alteredTbx1andVegfr3gene dosage, and we show that this likely results from an earlier requirement forTbx1in ventral cardiac LEC progenitors.

[发布日期] 2020-11-01

[关键词] 2ND HEART;TBX1;VEGFR3;ANGIOGENESIS;EXPRESSION;GROWTH;CELLS;CRE;ENDOTHELIUM;LYMPHATICS