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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\u2010of\u2010function genetics and transgenesis in the mouse, we show here a strong genetic interaction between\n                    <jats:italic>Tbx1<\/jats:italic>\n                    and\n                    <jats:italic>Vegfr3<\/jats:italic>\n                    in cardiac lymphangiogenesis. Intriguingly, we found that different aspects of the cardiac lymphatic phenotype in\n                    <jats:italic>Tbx1\u2010Vegfr3<\/jats:italic>\n                    compound heterozygotes were regulated independently by the two genes, with\n                    <jats:italic>Tbx1<\/jats:italic>\n                    primarily regulating vessel numbers and\n                    <jats:italic>Vegfr3<\/jats:italic>\n                    vessel morphology. Consistent with this observation,\n                    <jats:italic>\n                      Tbx1\n                      <jats:sup>Cre<\/jats:sup>\n                    <\/jats:italic>\n                    \u2010activated expression of a\n                    <jats:italic>Vegfr3<\/jats:italic>\n                    transgene rescued partially the cardiac lymphatic abnormalities in compound heterozygotes. Through time\u2010controlled genetic experiments, we show that\n                    <jats:italic>Tbx1<\/jats:italic>\n                    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\n                    <jats:italic>Tbx1<\/jats:italic>\n                    and\n                    <jats:italic>Vegfr3<\/jats:italic>\n                    gene dosage, and we show that this likely results from an earlier requirement for\n                    <jats:italic>Tbx1<\/jats:italic>\n                    in ventral cardiac LEC progenitors.\n                  <\/jats:p>","DOI":"10.1096\/fj.201902202r","type":"journal-article","created":{"date-parts":[[2020,9,20]],"date-time":"2020-09-20T03:36:14Z","timestamp":1600572974000},"page":"15062-15079","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["A dual role for\n                    <i>Tbx1<\/i>\n                    in cardiac lymphangiogenesis through genetic interaction with\n                    <i>Vegfr3<\/i>"],"prefix":"10.1096","volume":"34","author":[{"given":"Stefania","family":"Martucciello","sequence":"first","affiliation":[{"name":"IRCCS Neuromed Pozzilli Italy"},{"name":"Department of Chemistry and Biology University of Salerno Fisciano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Giuseppina","family":"Turturo","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u201cABT\u201d CNR Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marchesa","family":"Bilio","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u201cABT\u201d CNR Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Cioffi","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u201cABT\u201d CNR Naples 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