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Development. 2019 Oct 3. pii: dev.184218. doi: 10.1242/dev.184218. [Epub ahead of print]

GATA2 controls lymphatic endothelial cell junctional integrity and lymphovenous valve morphogenesis through miR-126.

Author information

1
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
2
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
3
Department of Biological Sciences and Center for Systems Biology, The University of Texas at Dallas, Richardson, TX, USA.
4
Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA.
5
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
6
Lymphology Laboratories, University of Arizona, Tuscon, Arizona, USA.
7
Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
8
Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.
9
Functional and Chemical Genomics Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
10
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA sathish-srinivasan@omrf.org.

Abstract

Mutations in the transcription factor GATA2 cause lymphedema. GATA2 is necessary for the development of lymphatic valves (LVs) and lymphovenous valves (LVVs), and for the patterning of lymphatic vessels. Here, we report that GATA2 is not necessary for valvular endothelial cell (VEC) differentiation. Instead, GATA2 is required for VEC maintenance and morphogenesis. GATA2 is also necessary for the expression of cell junction molecules VE-Cadherin and Claudin5 in lymphatic vessels. We identified miR-126 as a target of GATA2, and miR-126 -/- embryos recapitulate the phenotypes of mice lacking GATA2. Primary human lymphatic endothelial cells (HLECs) lacking GATA2 (GATA2 ΔHLEC ) have altered expression of Claudin5 and VE-Cadherin, and blocking miR-126 activity in HLECs phenocopies these changes in expression. Importantly, overexpression of miR-126 in GATA2 ΔHLEC significantly rescues the cell junction defects. Thus, our work defines a new mechanism of GATA2 and uncovers miR-126 as a novel regulator of mammalian lymphatic vascular development.

KEYWORDS:

Claudin5; GATA2; Lymphatic vasculature; Lymphovenous valves; MiR-126; VE-Cadherin

PMID:
31582413
DOI:
10.1242/dev.184218
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