GATA2 is required for lymphatic vessel valve development and maintenance.

Details

Ressource 1Download: JCI78888.pdf (10122.73 [Ko])
State: Public
Version: Final published version
Serval ID
serval:BIB_7CE1E8B0E0BD
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
GATA2 is required for lymphatic vessel valve development and maintenance.
Journal
Journal of Clinical Investigation
Author(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
Publication state
Published
Issued date
2015
Peer-reviewed
Oui
Volume
125
Number
8
Pages
2979-2994
Language
english
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.
Pubmed
Web of science
Open Access
Yes
Create date
28/08/2015 17:33
Last modification date
20/08/2019 14:38
Usage data