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Molecular and Cellular Biology, January 2005, p. 336-345, Vol. 25, No. 1
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.1.336-345.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Targeted Deletion of mek5 Causes Early Embryonic Death and Defects in the Extracellular Signal-Regulated Kinase 5/Myocyte Enhancer Factor 2 Cell Survival Pathway

Xin Wang,1 Anita J. Merritt,1 Jan Seyfried,1 Chun Guo,2 Emmanouil S. Papadakis,1 Katherine G. Finegan,1 Midori Kayahara,1 Jill Dixon,1 Raymond P. Boot-Handford,2 Elizabeth J. Cartwright,3 Ulrike Mayer,2 and Cathy Tournier1*

School of Biological Sciences,1 Wellcome Trust Center for Cell Matrix,2 School of Medicine, University of Manchester, Manchester, United Kingdom3

Received 18 June 2004/ Returned for modification 24 August 2004/ Accepted 3 October 2004

To elucidate the physiological significance of MEK5 in vivo, we have examined the effect of mek5 gene elimination in mice. Heterozygous mice appear to be healthy and were fertile. However, mek5–/– embryos die at approximately embryonic day 10.5 (E10.5). The phenotype of the mek5–/– embryos includes abnormal cardiac development as well as a marked decrease in proliferation and an increase in apoptosis in the heart, head, and dorsal regions of the mutant embryos. The absence of MEK5 does not affect cell cycle progression but sensitizes mouse embryonic fibroblasts (MEFs) to the ability of sorbitol to enhance caspase 3 activity. Further studies with mek5–/– MEFs indicate that MEK5 is required for mediating extracellular signal-regulated kinase 5 (ERK5) activation and for the regulation of the transcriptional activity of myocyte enhancer factor 2. Overall, this is the first study to rigorously establish the role of MEK5 in vivo as an activator of ERK5 and as an essential regulator of cell survival that is required for normal embryonic development.

* Corresponding author. Mailing address: University of Manchester, The Michael Smith Building, Oxford Rd., Manchester M13 9PT, United Kingdom. Phone: 44 161 275 5417. Fax: 44 161 275 5082. E-mail: cathy.tournier{at}man.ac.uk.

Molecular and Cellular Biology, January 2005, p. 336-345, Vol. 25, No. 1
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.1.336-345.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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