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

^*Corresponding author for this work

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

44 Citations (Scopus)

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
DOIs	https://doi.org/10.1016/j.celrep.2015.12.049
Publication status	Published - 26 Jan 2016
Externally published	Yes

Keywords

4-hydroxytamoxifen
4-OHT
Embryonic stem cells
ES cells
MEF
Mouse embryonic fibroblasts
NCCs
Neural crest cells
PKC
PKN
Protein kinase C
Protein kinase N

UN SDGs

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

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10.1016/j.celrep.2015.12.049Licence: CC BY

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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{1fdcb6d1be3f49f3b2cae0e251d36cae,

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 = "4-hydroxytamoxifen, 4-OHT, Embryonic stem cells, ES cells, MEF, Mouse embryonic fibroblasts, NCCs, Neural crest cells, PKC, PKN, Protein kinase C, Protein kinase N",

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.}",

note = "Funding Information: We thank Cancer Research UK, Barts Cancer Institute, HEFCE, the Wellcome Trust (087525 to A.J.C.), and the Royal Society for funding; Lucy Collinson and Electron Microscopy for imaging; the Crick BRF staff for animal studies; and Natalia Kazakova for ESC help. Funding Information: We thank Cancer Research UK, Barts Cancer Institute, HEFCE, the Wellcome Trust (087525 to A.J.C.), and the Royal Society for funding; Lucy Collinson and Electron Microscopy for imaging; the Crick BRF staff for animal studies; and Natalia Kazakova for ESC help. Publisher Copyright: {\textcopyright} 2016 The Authors.",

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 = "Cell Press",

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.

N1 - Funding Information: We thank Cancer Research UK, Barts Cancer Institute, HEFCE, the Wellcome Trust (087525 to A.J.C.), and the Royal Society for funding; Lucy Collinson and Electron Microscopy for imaging; the Crick BRF staff for animal studies; and Natalia Kazakova for ESC help. Funding Information: We thank Cancer Research UK, Barts Cancer Institute, HEFCE, the Wellcome Trust (087525 to A.J.C.), and the Royal Society for funding; Lucy Collinson and Electron Microscopy for imaging; the Crick BRF staff for animal studies; and Natalia Kazakova for ESC help. Publisher Copyright: © 2016 The Authors.

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 - 4-hydroxytamoxifen

KW - 4-OHT

KW - Embryonic stem cells

KW - ES cells

KW - MEF

KW - Mouse embryonic fibroblasts

KW - NCCs

KW - Neural crest cells

KW - PKC

KW - PKN

KW - Protein kinase C

KW - Protein kinase N

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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

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