University of Massachusetts Medical School Faculty Publications
UMMS Affiliation
Program in Molecular Medicine; UMass Metabolic Network
Publication Date
2016-05-31
Document Type
Article
Disciplines
Cell Biology | Cellular and Molecular Physiology | Developmental Biology
Abstract
The molecular mechanisms underlying lymphatic vascular development and function are not well understood. Recent studies have suggested a role for endothelial cell (EC) mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) in developmental angiogenesis and atherosclerosis. Here, we show that constitutive loss of EC Map4k4 in mice causes postnatal lethality due to chylothorax, suggesting that Map4k4 is required for normal lymphatic vascular function. Mice constitutively lacking EC Map4k4 displayed dilated lymphatic capillaries, insufficient lymphatic valves, and impaired lymphatic flow; furthermore, primary ECs derived from these animals displayed enhanced proliferation compared with controls. Yeast 2-hybrid analyses identified the Ras GTPase-activating protein Rasa1, a known regulator of lymphatic development and lymphatic endothelial cell fate, as a direct interacting partner for Map4k4. Map4k4 silencing in ECs enhanced basal Ras and extracellular signal-regulated kinase (Erk) activities, and primary ECs lacking Map4k4 displayed enhanced lymphatic EC marker expression. Taken together, these results reveal that EC Map4k4 is critical for lymphatic vascular development by regulating EC quiescence and lymphatic EC fate.
Rights and Permissions
Publisher PDF posted as allowed by the publisher's author rights policy at http://journals.asm.org/site/misc/ASM_Author_Statement.xhtml.
DOI of Published Version
10.1128/MCB.01121-15
Source
Mol Cell Biol. 2016 May 31;36(12):1740-9. doi: 10.1128/MCB.01121-15. Print 2016 Jun 15. Link to article on publisher's site
Related Resources
Journal/Book/Conference Title
Molecular and cellular biology
PubMed ID
27044870
Repository Citation
Roth Flach, Rachel J.; Guo, Chang-An; Danai, Laura V.; Yawe, Joseph C.; Gujja, Sharvari; Edwards, Yvonne J.K.; and Czech, Michael P., "Endothelial Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Is Critical for Lymphatic Vascular Development and Function" (2016). University of Massachusetts Medical School Faculty Publications. 1057.
https://escholarship.umassmed.edu/faculty_pubs/1057
Included in
Cell Biology Commons, Cellular and Molecular Physiology Commons, Developmental Biology Commons