The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
GATA2 is required for lymphatic vessel valve development and maintenance
Open accessAbstract
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.
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Cites
Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing
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“Monomethylation of H3K4Me1, a mark indicative of active or poised enhancer elements (59), was associated with the PROX1 –11 kb locus in hLECs and, to a lesser extent, in hBEC; however, it was not present in K562 cells, an erythroid cell line negative for PROX1.”
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Self-citationTranscriptional activation and DNA binding by the erythroid factor GF-1/NF-E1/Eryf 1.
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Self-citationDevelopment of heart valves requires Gata4 expression in endothelial-derived cells
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Notch signaling functions in lymphatic valve formation
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“These valve-forming cells reorient themselves with respect to the longitudinal axis of the vessel, extend into the vessel lumen, and form elongated valve leaflets composed of a bilayer of endothelial cells sandwiching an extracellular matrix core composed largely of Fibronectin-EIIIA (FN-EIIIA), laminin-α 5, and EMILI…”
Influential
Cited by
Vascular heterogeneity and specialization in development and disease
Potente, M., & Mäkinen, T. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.36 · Cited by 653
Lymphatic pumping: mechanics, mechanisms and malfunction
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Lymphatic Vessel Network Structure and Physiology
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The lymphatic system: integral roles in immunity
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Frye, M., Taddei, A., Dierkes, C., Martinez-Corral, I., Fielden, M., Ortsäter, H., Kazenwadel, J., Calado, D. P., Ostergaard, P., Salminen, M., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03959-6 · Cited by 169
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Metadata
- Authors
- 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.
- Venue
- Journal of Clinical Investigation
- Published
- 2015-07-27
- Volume
- 125
- Issue
- 8
- Pages
- 2979-2994
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2164257043
- Cited by
- 233
- References
- 9
- FWCI
- 7.54
- Type
- journal article
- Language
- en
- Open access
- bronze
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- 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. (2015). GATA2 is required for lymphatic vessel valve development and maintenance. Journal of Clinical Investigation. https://doi.org/10.1172/jci78888
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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