title: WNK1 protein kinase regulates embryonic cardiovascular development through the OSR1 signaling cascade.
abstract: WNK1 is a widely expressed serine/threonine protein kinase that regulates multiple cellular and organ functions via diverse mechanisms. We previously reported that endothelial-specific deletion of Wnk1 in mice results in embryonic lethality, with angiogenesis and cardiac defects beginning at embryonic day ∼10.5. Here, we further investigated the signaling mechanism by which WNK1 regulates embryonic cardiovascular development. We found that mice with a global deletion of Osr1, which encodes oxidative stress-responsive kinase-1, a protein kinase activated by WNK1, died in utero beginning at embryonic day ∼11. The defects in Osr1-null yolk sacs and embryos were virtually identical to those observed in Wnk1-knock-out mice: no mature large vessels in yolk sacs, defective angiogenesis in the brain and intersomitic vessels, and smaller chambers and reduced myocardial trabeculation in mutant hearts. Endothelial-specific deletion of Osr1 generated by crossing Osr1(flox/flox) mice with Tie2-Cre mice phenocopied defects caused by global Osr1 deletion. To investigate whether OSR1 acts downstream of WNK1 in embryonic angiogenesis, we generated a mouse line that carries a catalytically and constitutively active human OSR1 transgene in the ROSA26 locus under the control of a cassette of floxed transcription stop codons. We found that endothelial-specific expression of the constitutively active mutant OSR1, generated by Tie2-Cre-mediated excision of floxed stop codons in the mutated ROSA26 locus, rescued angiogenesis and cardiac defects in global Wnk1-null embryos. These results indicate that WNK1 activation of the OSR1 signaling cascade is an essential pathway that regulates angiogenesis and cardiac formation during mouse embryo development.
authors: Department of Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8856.
authors: Jian
authors: J
authors: Xie
authors: Department of Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8856.
authors: Joonho
authors: J
authors: Yoon
authors: Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan.
authors: Sung-Sen
authors: SS
authors: Yang
authors: Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan.
authors: Shih-Hua
authors: SH
authors: Lin
authors: Department of Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8856. Electronic address: chou-long.huang@utsouthwestern.edu.
authors: Chou-Long
authors: CL
authors: Huang
mesh_terms: D000483:Alleles; D000818:Animals; D018376:Cardiovascular Abnormalities / Q000196:embryology / Q000235:genetics; D002319:Cardiovascular System / Q000196:embryology / Q000201:enzymology / Q000473:pathology; D004622:Embryo, Mammalian / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D005804:Genes, Lethal; D006321:Heart / Q000196:embryology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D018919:Neovascularization, Physiologic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D015398:Signal Transduction; D000076204:WNK Lysine-Deficient Protein Kinase 1
chemical_list: D015778:Minor Histocompatibility Antigens; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C118135:OXSR1 protein, human; C534421:OXSR1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498744:Wnk1 protein, mouse
references: Physiol Rev. 2011 Jan;91(1):177-219
references: 21248166
references: Annu Rev Cell Dev Biol. 1995;11:73-91
references: 8689573
references: Oncogene. 2001 Sep 6;20(39):5562-9
references: 11571656
references: J Cell Biol. 1999 Nov 15;147(4):831-44
references: 10562284
references: J Biol Chem. 2004 Mar 19;279(12):11129-36
references: 14707132
references: J Clin Invest. 2007 Apr;117(4):1078-87
references: 17380208
references: Am J Physiol Cell Physiol. 2010 Sep;299(3):C614-20
references: 20463172
references: Biochem J. 2010 Jan 15;425(3):465-73
references: 20070256
references: Curr Biol. 2011 Dec 6;21(23):1979-87
references: 22119528
references: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14109-14
references: 14610273
references: J Biol Chem. 2000 Jun 2;275(22):16795-801
references: 10828064
references: J Cell Sci. 2008 Apr 1;121(Pt 7):989-1001
references: 18319301
references: Nat Genet. 1999 Jun;22(2):192-5
references: 10369265
references: Cell Signal. 2009 Dec;21(12):1727-37
references: 19720142
references: Biochem J. 2005 Oct 1;391(Pt 1):17-24
references: 16083423
references: Science. 2001 Aug 10;293(5532):1107-12
references: 11498583
references: Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10315-20
references: 16006511
references: Nature. 2005 Dec 15;438(7070):937-45
references: 16355211
references: Biochem J. 2008 Jan 15;409(2):321-31
references: 18092945
references: Dev Biol. 2001 Feb 15;230(2):230-42
references: 11161575
references: Am J Pathol. 2009 Sep;175(3):1315-27
references: 19644017
references: Mamm Genome. 2011 Jun;22(5-6):306-17
references: 21499899
references: Nature. 2005 May 5;435(7038):98-104
references: 15875024
references: Cell. 1998 May 29;93(5):741-53
references: 9630219
references: BMC Dev Biol. 2001;1:4
references: 11299042
references: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5434-9
references: 10779555
references: J Biol Chem. 2005 Dec 30;280(52):42685-93
references: 16263722
references: Cell. 1996 Dec 27;87(7):1153-5
references: 8980221
references: J Biol Chem. 2004 Feb 27;279(9):7826-31
references: 14681216
references: Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):10883-8
references: 16832045
references: Mech Dev. 2009 Aug-Sep;126(8-9):710-20
references: 19464366
references: EMBO Mol Med. 2010 Feb;2(2):63-75
references: 20091762
references: J Biol Chem. 1998 Oct 30;273(44):29150-5
references: 9786924
references: Proc Natl Acad Sci U S A. 2011 Oct 18;108(42):17538-43
references: 21972418