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

Md Riaj Mahamud,Yuenhee Kim,Greggory Myers,James Douglas Engel,Lijuan Chen,Shusheng Wang,Jing Ma,Xin Geng,Hong Chen,Boksik Cha,Dongwon Choi,Gaurav K Varshney ,Debbie J Mustacich ,Kim Chew Lim ,Sally A Camper ,Yen Chun Ho ,Tae Hoon Kim ,Marlys H Witte ,Young Kwon Hong ,Ramesh Srinivasan

doi:10.1242/dev.184218

Abstract

ABSTRACTMutations in the transcription factor GATA2 cause lymphedema. GATA2 is necessary for the development of lymphatic valves and lymphovenous valves, 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 the cell junction molecules VE-cadherin and claudin 5 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 (HLECΔGATA2) have altered expression of claudin 5 and VE-cadherin, and blocking miR-126 activity in HLECs phenocopies these changes in expression. Importantly, overexpression of miR-126 in HLECΔGATA2 significantly rescues the cell junction defects. Thus, our work defines a new mechanism of GATA2 activity and uncovers miR-126 as a novel regulator of mammalian lymphatic vascular development.

Highlights

The lymphatic vasculature is a hierarchically organized tissue that absorbs and returns extravasated plasma fluids and digested lipids to the blood circulation (Chen et al, 2014; Tammela and Alitalo, 2010)
Thin sections of lymphovenous valves (LVVs)-ECs from E12.0 control and Gata2LECKO embryos did not reveal any obvious differences in VE-cadherin or DISCUSSION In this work, we have discovered that GATA2 is not necessary for LVV-EC differentiation, it is required for their maintenance
GATA2 is important for LVV-ECs and lymphatic endothelial cells (LECs) to align appropriately with respect to the direction of fluid flow

Summary

Introduction

The lymphatic vasculature is a hierarchically organized tissue that absorbs and returns extravasated plasma fluids and digested lipids to the blood circulation (Chen et al, 2014; Tammela and Alitalo, 2010). This fluid, commonly known as lymph, is absorbed by lymphatic capillaries and transported via collecting lymphatic. Other lymphatic anomalies include chylous ascites (fluid in the peritoneal cavity), chylothorax (fluid around the lungs) or lymph reflex These lymphatic vascular dysfunctions could arise from anatomical defects in the vessels or valves, though in most cases the precise cause is unclear

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