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

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{Delta}HLEC) 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{Delta}HLEC 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.\n\nNon-standard abbreviationsLECs, lymphatic endothelial cells; LVs, lymphatic valves; LV-ECs, lymphatic valve-forming endothelial cells; LVVs, lymphovenous valves; LVV-ECs, lymphovenous valve-forming endothelial cells; HLEC, primary human LECs; OSS, Oscillatory shear stress; IHC, immunohistochemistry.