Journal article
WNK1 Protein Kinase Regulates Embryonic Cardiovascular Development through the OSR1 Signaling Cascade
The Journal of biological chemistry, Vol.288(12), pp.8566-8574
03/22/2013
DOI: 10.1074/jbc.M113.451575
PMCID: PMC3605675
PMID: 23386621
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 Osr1flox/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.
Background: WNK1 is critical for embryonic cardiovascular development.
Results: A global deletion of Osr1 in mice phenocopies the Wnk1 deletion; expression of the constitutively active mutant OSR1 rescues developmental defects in Wnk1-null embryos.
Conclusion: WNK1 activation of OSR1 is essential for mouse embryo development.
Significance: The WNK1-OSR1 signaling cascade is a novel pathway that regulates embryonic angiogenesis and cardiac formation.
Details
- Title: Subtitle
- WNK1 Protein Kinase Regulates Embryonic Cardiovascular Development through the OSR1 Signaling Cascade
- Creators
- Jian Xie - Department of Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8856Joonho Yoon - Department of Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8856Sung-Sen Yang - Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, TaiwanShih-Hua Lin - Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, TaiwanChou-Long Huang - Department of Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8856
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.288(12), pp.8566-8574
- DOI
- 10.1074/jbc.M113.451575
- PMID
- 23386621
- PMCID
- PMC3605675
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 03/22/2013
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984094538002771
Metrics
17 Record Views