1. Knockout of the PKN Family of Rho Effector Kinases Reveals a Non-redundant Role for PKN2 in Developmental Mesoderm Expansion
- Author
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Quétier I, Jj, Marshall, Spencer-Dene B, Lachmann S, Casamassima A, Franco C, Escuin S, Jt, Worrall, Baskaran P, Rajeeve V, Howell M, Aj, Copp, Stamp G, Rosewell I, Cutillas P, Holger Gerhardt, Pj, Parker, Aj, Cameron, and Repositório da Universidade de Lisboa
- Subjects
Embryonic stem cells ,animal structures ,Protein Kinase C/deficiency ,mouse embryonic fibroblasts ,Myocardium/metabolism ,Embryonic Development ,Antineoplastic Agents ,Apoptosis ,Cell Movement/drug effects ,Heart/growth & development ,Cell Line ,Protein kinase N ,Mesoderm ,Cell Proliferation/drug effects ,Mice ,Cell Movement ,Genes, Reporter ,Report ,Animals ,PKC ,lcsh:QH301-705.5 ,Cell Proliferation ,Embryonic Development/drug effects ,Mice, Knockout ,neural crest cells ,MEF ,Myocardium ,Apoptosis/drug effects ,Heart ,Embryo, Mammalian ,ES cells ,PKN ,4-hydroxytamoxifen ,Tamoxifen/analogs & derivatives ,Mice, Inbred C57BL ,Tamoxifen ,Embryo, Mammalian/cytology ,lcsh:Biology (General) ,Mesoderm/cytology ,Cardiovascular and Metabolic Diseases ,embryonic structures ,Microscopy, Electron, Scanning ,NCCs ,4-OHT ,Antineoplastic Agents/pharmacology ,protein kinase C - Abstract
Summary In animals, the protein kinase C (PKC) family has expanded into diversely regulated subgroups, including the Rho family-responsive PKN kinases. Here, we describe knockouts of all three mouse PKN isoforms and reveal that PKN2 loss results in lethality at embryonic day 10 (E10), with associated cardiovascular and morphogenetic defects. The cardiovascular phenotype was not recapitulated by conditional deletion of PKN2 in endothelial cells or the developing heart. In contrast, inducible systemic deletion of PKN2 after E7 provoked collapse of the embryonic mesoderm. Furthermore, mouse embryonic fibroblasts, which arise from the embryonic mesoderm, depend on PKN2 for proliferation and motility. These cellular defects are reflected in vivo as dependence on PKN2 for mesoderm proliferation and neural crest migration. We conclude that failure of the mesoderm to expand in the absence of PKN2 compromises cardiovascular integrity and development, resulting in lethality., Graphical Abstract, Highlights • PKN2, but not PKN1 or PKN3, is essential during mouse embryogenesis • PKN2 knockout causes severe cardiovascular and morphogenetic abnormalities • PKN2 is required for mesenchymal growth and neural crest migration in vivo, The Rho effector PKN kinases regulate diverse cellular functions, but their in vivo function is unexplored. By systematically targeting the PKN family, Quetier et al. reveal a unique role for PKN2 during developmental growth and morphogenesis. These findings impact on developmental disorders and the targeting of PKN in disease.
- Published
- 2016
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