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

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

Research output: Contribution to journalArticle

Abstract

Mutations 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.

Original languageEnglish (US)
Article numberdev184218
JournalDevelopment (Cambridge)
Volume146
Issue number21
DOIs
StatePublished - Jan 1 2019

Keywords

  • Claudin 5
  • GATA2
  • Lymphatic vasculature
  • Lymphovenous valves
  • MIR-126
  • VE-cadherin

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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  • Cite this

    Riaj Mahamud, M., Geng, X., Ho, Y. C., Cha, B., Kim, Y., Ma, J., Chen, L., Myers, G., Camper, S., Mustacich, D., Witte, M., Choi, D., Hong, Y. K., Chen, H., Varshney, G., Engel, J. D., Wang, S., Kim, T. H., Lim, K. C., & Sathish Srinivasan, R. (2019). GATA2 controls lymphatic endothelial cell junctional integrity and lymphovenous valve morphogenesis through MIR-126. Development (Cambridge), 146(21), [dev184218]. https://doi.org/10.1242/dev.184218