Knockout of the PKN Family of Rho Effector Kinases Reveals a Non-redundant Role for PKN2 in Developmental Mesoderm Expansion

Ivan Quétier; Jacqueline J T Marshall; Bradley Spencer-Dene; Sylvie Lachmann; Adele Casamassima; Claudio Franco; Sarah Escuin; Joseph T Worrall; Priththivika Baskaran; Vinothini Rajeeve; Michael Howell; Andrew J Copp; Gordon Stamp; Ian Rosewell; Pedro Cutillas; Holger Gerhardt; Peter J Parker; Angus J M Cameron

doi:10.1016/j.celrep.2015.12.049

Knockout of the PKN Family of Rho Effector Kinases Reveals a Non-redundant Role for PKN2 in Developmental Mesoderm Expansion

Ivan Quétier, Jacqueline J T Marshall, Bradley Spencer-Dene, Sylvie Lachmann, Adele Casamassima, Claudio Franco, Sarah Escuin, Joseph T Worrall, Priththivika Baskaran, Vinothini Rajeeve, Michael Howell, Andrew J Copp, Gordon Stamp, Ian Rosewell, Pedro Cutillas, Holger Gerhardt, Peter J Parker, Angus J M Cameron

Comprehensive Cancer Centre

Kinase Biology Laboratory, John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
Francis Crick Institute
Instituto Medicina Molecular (iMM), Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisbon, Portugal.
UCL University College London
Spatial Signalling Team, Centre for Tumour Biology, Barts Cancer Institute-A Cancer Research UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
Kinase Biology Laboratory, John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Electronic address: [email protected].

Research output: Contribution to journal › Article › peer-review

45 Citations (Scopus)

136 Downloads (Pure)

Abstract

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.

Original language	English
Pages (from-to)	440-448
Number of pages	9
Journal	Cell Reports
Volume	14
Issue number	3
Early online date	7 Jan 2016
DOIs	https://doi.org/10.1016/j.celrep.2015.12.049
Publication status	Published - 26 Jan 2016

Keywords

Animals
Antineoplastic Agents/pharmacology
Apoptosis/drug effects
Cell Line
Cell Movement/drug effects
Cell Proliferation/drug effects
Embryo, Mammalian/cytology
Embryonic Development/drug effects
Genes, Reporter
Heart/growth & development
Mesoderm/cytology
Mice
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Electron, Scanning
Myocardium/metabolism
Protein Kinase C/deficiency
Tamoxifen/analogs & derivatives

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.celrep.2015.12.049Licence: CC BY

Knockout of the PKN_QUETIER_Published 26 January 2016_GOLD VoR (CC BY_Final published version, 3.22 MBLicence: CC BY

Cite this

Quétier, I., Marshall, J. J. T., Spencer-Dene, B., Lachmann, S., Casamassima, A., Franco, C., Escuin, S., Worrall, J. T., Baskaran, P., Rajeeve, V., Howell, M., Copp, A. J., Stamp, G., Rosewell, I., Cutillas, P., Gerhardt, H., Parker, P. J., & Cameron, A. J. M. (2016). Knockout of the PKN Family of Rho Effector Kinases Reveals a Non-redundant Role for PKN2 in Developmental Mesoderm Expansion. Cell Reports, 14(3), 440-448. https://doi.org/10.1016/j.celrep.2015.12.049

@article{92725ae1e33941f097e6fe9f15ab038f,

title = "Knockout of the PKN Family of Rho Effector Kinases Reveals a Non-redundant Role for PKN2 in Developmental Mesoderm Expansion",

abstract = "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. ",

keywords = "Animals, Antineoplastic Agents/pharmacology, Apoptosis/drug effects, Cell Line, Cell Movement/drug effects, Cell Proliferation/drug effects, Embryo, Mammalian/cytology, Embryonic Development/drug effects, Genes, Reporter, Heart/growth & development, Mesoderm/cytology, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Electron, Scanning, Myocardium/metabolism, Protein Kinase C/deficiency, Tamoxifen/analogs & derivatives",

author = "Ivan Qu{\'e}tier and Marshall, {Jacqueline J T} and Bradley Spencer-Dene and Sylvie Lachmann and Adele Casamassima and Claudio Franco and Sarah Escuin and Worrall, {Joseph T} and Priththivika Baskaran and Vinothini Rajeeve and Michael Howell and Copp, {Andrew J} and Gordon Stamp and Ian Rosewell and Pedro Cutillas and Holger Gerhardt and Parker, {Peter J} and Cameron, {Angus J M}",

year = "2016",

month = jan,

day = "26",

doi = "10.1016/j.celrep.2015.12.049",

language = "English",

volume = "14",

pages = "440--448",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Elsevier BV",

number = "3",

}

Quétier, I, Marshall, JJT, Spencer-Dene, B, Lachmann, S, Casamassima, A, Franco, C, Escuin, S, Worrall, JT, Baskaran, P, Rajeeve, V, Howell, M, Copp, AJ, Stamp, G, Rosewell, I, Cutillas, P, Gerhardt, H, Parker, PJ & Cameron, AJM 2016, 'Knockout of the PKN Family of Rho Effector Kinases Reveals a Non-redundant Role for PKN2 in Developmental Mesoderm Expansion', Cell Reports, vol. 14, no. 3, pp. 440-448. https://doi.org/10.1016/j.celrep.2015.12.049

TY - JOUR

T1 - Knockout of the PKN Family of Rho Effector Kinases Reveals a Non-redundant Role for PKN2 in Developmental Mesoderm Expansion

AU - Quétier, Ivan

AU - Marshall, Jacqueline J T

AU - Spencer-Dene, Bradley

AU - Lachmann, Sylvie

AU - Casamassima, Adele

AU - Franco, Claudio

AU - Escuin, Sarah

AU - Worrall, Joseph T

AU - Baskaran, Priththivika

AU - Rajeeve, Vinothini

AU - Howell, Michael

AU - Copp, Andrew J

AU - Stamp, Gordon

AU - Rosewell, Ian

AU - Cutillas, Pedro

AU - Gerhardt, Holger

AU - Parker, Peter J

AU - Cameron, Angus J M

PY - 2016/1/26

Y1 - 2016/1/26

N2 - 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.

AB - 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.

KW - Animals

KW - Antineoplastic Agents/pharmacology

KW - Apoptosis/drug effects

KW - Cell Line

KW - Cell Movement/drug effects

KW - Cell Proliferation/drug effects

KW - Embryo, Mammalian/cytology

KW - Embryonic Development/drug effects

KW - Genes, Reporter

KW - Heart/growth & development

KW - Mesoderm/cytology

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Microscopy, Electron, Scanning

KW - Myocardium/metabolism

KW - Protein Kinase C/deficiency

KW - Tamoxifen/analogs & derivatives

U2 - 10.1016/j.celrep.2015.12.049

DO - 10.1016/j.celrep.2015.12.049

M3 - Article

C2 - 26774483

SN - 2211-1247

VL - 14

SP - 440

EP - 448

JO - Cell Reports

JF - Cell Reports

IS - 3

ER -

Knockout of the PKN Family of Rho Effector Kinases Reveals a Non-redundant Role for PKN2 in Developmental Mesoderm Expansion

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this