title: Bone morphogenetic protein 2 signaling negatively modulates lymphatic development in vertebrate embryos.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: William P
authors.initials: WP
authors.lastname: Dunworth
authors.forename: Jose
authors.initials: J
authors.lastname: Cardona-Costa
authors.forename: Esra Cagavi
authors.initials: EC
authors.lastname: Bozkulak
authors.forename: Jun-Dae
authors.initials: JD
authors.lastname: Kim
authors.forename: Stryder
authors.initials: S
authors.lastname: Meadows
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Fischer
authors.forename: Yeqi
authors.initials: Y
authors.lastname: Wang
authors.forename: Ondine
authors.initials: O
authors.lastname: Cleaver
authors.forename: Yibing
authors.initials: Y
authors.lastname: Qyang
authors.forename: Elke A
authors.initials: EA
authors.lastname: Ober
authors.forename: Suk-Won
authors.initials: SW
authors.lastname: Jin
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D058732:Embryoid Bodies / Q000166:cytology / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004729:Endothelium, Lymphatic / Q000196:embryology* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D042601:Lymphatic Vessels / Q000196:embryology / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D018398:Homeodomain Proteins; D035683:MicroRNAs; D051785:Smad Proteins; D025521:Tumor Suppressor Proteins; D029961:Zebrafish Proteins; C405936:bmp2b protein, zebrafish; D000098551:Prospero-Related Homeobox 1 Protein
keywords: BMP2 protein; developmental biology; lymphatic vessels; microRNAs