ena-STUDY-CENTRE FOR CANCER BIOLOGY-22-05-2015-07:39:12:133-174
GATA2 haploinsufficiency predisposing to lymphedema reveals key roles in lymphatic vascular development.
Heterozygous germline mutations in the zinc finger transcription factor GATA2 have recently been shown to underlie a broad range of clinical phenotypes including Emberger syndrome, a disorder characterised by lymphedema and predisposition to myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). Though GATA2 has well defined roles in hematopoiesis, the functions of GATA2 in the lymphatic vasculature and the mechanisms by which GATA2 mutations result in lymphedema have not been characterized. Here, we provide a molecular explanation for the predisposition of a subset of patients with germline GATA2 mutations to developing lymphedema, by demonstrating that GATA2 missense Emberger mutations are complete loss-of-function alleles with respect to their capacity to regulate the transcription of genes important for lymphatic vessel valve development. We identify a novel putative enhancer element upstream of the key lymphatic transcriptional regulator PROX1, that is bound by GATA2, FOXC2 and NFATC1 and determine that this enhancer is subject to differential epigenetic regulation in lymphatic, compared to blood vascular endothelial cells. GATA2 missense Emberger mutants were found to have a profoundly reduced capacity to bind this element. Conditional deletion of Gata2 in mice revealed that Gata2 is crucial for the development of both lymphovenous and lymphatic vessel valves. Moreover, heterozygous Gata2 mutant mice exhibited dysmorphic lymphatic vessels and defective lymphatic vascular transport. Our data reveal crucial roles for Gata2 in lymphatic vessel and valve morphogenesis and provide a molecular and genetic framework to explain why a select catalogue of human GATA2 mutations results in lymphedema
Heterozygous germline mutations in the zinc finger transcription factor GATA2 have recently been shown to underlie a broad range of clinical phenotypes including Emberger syndrome, a disorder characterised by lymphedema and predisposition to myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). Though GATA2 has well defined roles in hematopoiesis, the functions of GATA2 in the lymphatic vasculature and the mechanisms by which GATA2 mutations result in lymphedema have not been characterized. Here, we provide a molecular explanation for the predisposition of a subset of patients with germline GATA2 mutations to developing lymphedema, by demonstrating that GATA2 missense Emberger mutations are complete loss-of-function alleles with respect to their capacity to regulate the transcription of genes important for lymphatic vessel valve development. We identify a novel putative enhancer element upstream of the key lymphatic transcriptional regulator PROX1, that is bound by GATA2, FOXC2 and NFATC1 and determine that this enhancer is subject to differential epigenetic regulation in lymphatic, compared to blood vascular endothelial cells. GATA2 missense Emberger mutants were found to have a profoundly reduced capacity to bind this element. Conditional deletion of Gata2 in mice revealed that Gata2 is crucial for the development of both lymphovenous and lymphatic vessel valves. Moreover, heterozygous Gata2 mutant mice exhibited dysmorphic lymphatic vessels and defective lymphatic vascular transport. Our data reveal crucial roles for Gata2 in lymphatic vessel and valve morphogenesis and provide a molecular and genetic framework to explain why a select catalogue of human GATA2 mutations results in lymphedema