Dunworth, William P2; Cardona-Costa, Jose3; Bozkulak, Esra Cagavi3; Kim, Jun-Dae3; Meadows, Stryder3; Fischer, Johanna C3; Wang, Yeqi3; Cleaver, Ondine3; Qyang, Yibing3; Ober, Elke A4; Jin, Suk-Won3
1 Laboratory, The Danish Stem Cell Center, Faculty of Health and Medical Sciences, Københavns Universitet2 From the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (W.P.D., J.C.-C., E.C.B., J.-D.K., Y.W., Y.Q., S-W.J.); MRC National Institute for Medical Research, Division of Developmental Biology, Mill Hill, London, United Kingdom (J.C.F., E.A.O.); and Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX (S.M., O.C.).3 unknown4 Laboratory, The Danish Stem Cell Center, Faculty of Health and Medical Sciences, Københavns Universitet
RATIONALE: The emergence of lymphatic endothelial cells (LECs) seems to be highly regulated during development. Although several factors that promote the differentiation of LECs in embryonic development have been identified, those that negatively regulate this process are largely unknown. OBJECTIVE: Our aim was to delineate the role of bone morphogenetic protein (BMP) 2 signaling in lymphatic development. METHODS AND RESULTS: BMP2 signaling negatively regulates the formation of LECs. Developing LECs lack any detectable BMP signaling activity in both zebrafish and mouse embryos, and excess BMP2 signaling in zebrafish embryos and mouse embryonic stem cell-derived embryoid bodies substantially decrease the emergence of LECs. Mechanistically, BMP2 signaling induces expression of miR-31 and miR-181a in a SMAD-dependent mechanism, which in turn results in attenuated expression of prospero homeobox protein 1 during development. CONCLUSIONS: Our data identify BMP2 as a key negative regulator for the emergence of the lymphatic lineage during vertebrate development.
Circulation Research, 2014, Vol 114, Issue 1, p. 56-66