title: GATA2 is required for lymphatic vessel valve development and maintenance.
abstract: Heterozygous germline mutations in the zinc finger transcription factor GATA2 have recently been shown to underlie a range of clinical phenotypes, including Emberger syndrome, a disorder characterized by lymphedema and predisposition to myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). Despite 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 have provided a molecular explanation for lymphedema predisposition in a subset of patients with germline GATA2 mutations. Specifically, we demonstrated that Emberger-associated GATA2 missense mutations result in complete loss of GATA2 function, with respect to the capacity to regulate the transcription of genes that are important for lymphatic vessel valve development. We identified a putative enhancer element upstream of the key lymphatic transcriptional regulator PROX1 that is bound by GATA2, and the transcription factors FOXC2 and NFATC1. Emberger GATA2 missense mutants had a profoundly reduced capacity to bind this element. Conditional Gata2 deletion in mice revealed that GATA2 is required for both development and maintenance of lymphovenous and lymphatic vessel valves. Together, our data unveil essential roles for GATA2 in the lymphatic vasculature and explain why a select catalogue of human GATA2 mutations results in lymphedema.
authors.forename: Jan
authors.initials: J
authors.lastname: Kazenwadel
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Betterman
authors.forename: Chan-Eng
authors.initials: CE
authors.lastname: Chong
authors.forename: Philippa H
authors.initials: PH
authors.lastname: Stokes
authors.forename: Young K
authors.initials: YK
authors.lastname: Lee
authors.forename: Genevieve A
authors.initials: GA
authors.lastname: Secker
authors.forename: Yan
authors.initials: Y
authors.lastname: Agalarov
authors.forename: Cansaran Saygili
authors.initials: CS
authors.lastname: Demir
authors.forename: David M
authors.initials: DM
authors.lastname: Lawrence
authors.forename: Drew L
authors.initials: DL
authors.lastname: Sutton
authors.forename: Sebastien P
authors.initials: SP
authors.lastname: Tabruyn
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Miura
authors.forename: Marjo
authors.initials: M
authors.lastname: Salminen
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Petrova
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Matthews
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Hahn
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Scott
authors.forename: Natasha L
authors.initials: NL
authors.lastname: Harvey
mesh_terms: D000818:Animals; D004742:Enhancer Elements, Genetic; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D042601:Lymphatic Vessels / Q000196:embryology* / Q000473:pathology; D008209:Lymphedema / Q000196:embryology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009154:Mutation; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D051858:Forkhead Transcription Factors; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C494712:Gata2 protein, mouse; D018398:Homeodomain Proteins; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; C494005:Nfatc1 protein, mouse; D025521:Tumor Suppressor Proteins; C082078:mesenchyme fork head 1 protein; D000098551:Prospero-Related Homeobox 1 Protein