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A dual role for Tbx1 in cardiac lymphangiogenesis through genetic interaction with Vegfr3
Author(s) -
Martucciello Stefania,
Turturo Maria Giuseppina,
Bilio Marchesa,
Cioffi Sara,
Chen Li,
Baldini Antonio,
Illingworth Elizabeth
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201902202r
Subject(s) - tbx1 , lymphangiogenesis , lymphatic system , biology , phenotype , heterozygote advantage , microbiology and biotechnology , gene , genetics , gene expression , immunology , allele , promoter , cancer , metastasis
The transcription factor TBX1 is 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 between Tbx1 and Vegfr3 in cardiac lymphangiogenesis. Intriguingly, we found that different aspects of the cardiac lymphatic phenotype in Tbx1‐Vegfr3 compound heterozygotes were regulated independently by the two genes, with Tbx1 primarily regulating vessel numbers and Vegfr3 vessel morphology. Consistent with this observation, Tbx1 Cre ‐activated expression of a Vegfr3 transgene rescued partially the cardiac lymphatic abnormalities in compound heterozygotes. Through time‐controlled genetic experiments, we show that Tbx1 is 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 altered Tbx1 and Vegfr3 gene dosage, and we show that this likely results from an earlier requirement for Tbx1 in ventral cardiac LEC progenitors.