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WNK1 protein kinase regulates embryonic cardiovascular development through the OSR1 signaling cascade.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2013 Mar 22; Vol. 288 (12), pp. 8566-8574. Date of Electronic Publication: 2013 Feb 05. - Publication Year :
- 2013
-
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.
- Subjects :
- Alleles
Animals
Cardiovascular Abnormalities embryology
Cardiovascular Abnormalities genetics
Cardiovascular System embryology
Cardiovascular System enzymology
Cardiovascular System pathology
Embryo, Mammalian blood supply
Embryo, Mammalian metabolism
Embryo, Mammalian pathology
Female
Gene Expression Regulation
Genes, Lethal
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Minor Histocompatibility Antigens
Neovascularization, Physiologic
Platelet Endothelial Cell Adhesion Molecule-1 metabolism
Protein Serine-Threonine Kinases biosynthesis
Protein Serine-Threonine Kinases genetics
Signal Transduction
WNK Lysine-Deficient Protein Kinase 1
Heart embryology
Protein Serine-Threonine Kinases metabolism
Protein Serine-Threonine Kinases physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 288
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 23386621
- Full Text :
- https://doi.org/10.1074/jbc.M113.451575