GATA2 is required for lymphatic vessel valve development and maintenance.

Détails

Ressource 1Télécharger: JCI78888.pdf (10122.73 [Ko])
Etat: Public
Version: Final published version
ID Serval
serval:BIB_7CE1E8B0E0BD
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
GATA2 is required for lymphatic vessel valve development and maintenance.
Périodique
Journal of Clinical Investigation
Auteur(s)
Kazenwadel J., Betterman K.L., Chong C.E., Stokes P.H., Lee Y.K., Secker G.A., Agalarov Y., Demir C.S., Lawrence D.M., Sutton D.L., Tabruyn S.P., Miura N., Salminen M., Petrova T.V., Matthews J.M., Hahn C.N., Scott H.S., Harvey N.L.
ISSN
1558-8238 (Electronic)
ISSN-L
0021-9738
Statut éditorial
Publié
Date de publication
2015
Peer-reviewed
Oui
Volume
125
Numéro
8
Pages
2979-2994
Langue
anglais
Résumé
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.
Pubmed
Web of science
Open Access
Oui
Création de la notice
28/08/2015 17:33
Dernière modification de la notice
20/08/2019 14:38
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