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; Anita J Merritt; Jan Seyfried; Chun Guo; Emmanouil S Papadakis; Katherine G Finegan; Midori Kayahara; Jill Dixon; Raymond P Boot-Handford; Elizabeth J Cartwright; Ulrike Mayer; Cathy Tournier

doi:10.1128/MCB.25.1.336-345.2005

Targeted deletion of mek5 causes early embryonic death and defects in the extracellular signal-regulated kinase 5/myocyte enhancer factor 2 cell survival pathway

Mol Cell Biol. 2005 Jan;25(1):336-45. doi: 10.1128/MCB.25.1.336-345.2005.

Authors

Xin Wang¹, Anita J Merritt, Jan Seyfried, Chun Guo, Emmanouil S Papadakis, Katherine G Finegan, Midori Kayahara, Jill Dixon, Raymond P Boot-Handford, Elizabeth J Cartwright, Ulrike Mayer, Cathy Tournier

Affiliation

¹ University of Manchester, The Michael Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Blotting, Southern
Caspase 3
Caspases / metabolism
Cell Death
Cell Proliferation
Cell Survival
Cells, Cultured
DNA-Binding Proteins / genetics*
Enzyme Activation
Fibroblasts / metabolism
Flow Cytometry
Gene Deletion
Genes, Reporter
Genetic Vectors
Genotype
Heterozygote
Immunoblotting
Immunohistochemistry
In Situ Nick-End Labeling
Luciferases / metabolism
MAP Kinase Kinase 5 / genetics*
MAP Kinase Kinase 5 / physiology*
MEF2 Transcription Factors
Mice
Mice, Knockout
Mitogen-Activated Protein Kinase 7 / genetics*
Models, Genetic
Mutation
Myocardium / metabolism
Myogenic Regulatory Factors
Phenotype
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Time Factors
Tissue Distribution
Transcription Factors / genetics*
Transcription, Genetic
Transcriptional Activation
Transgenes

Substances

DNA-Binding Proteins
MEF2 Transcription Factors
Myogenic Regulatory Factors
Transcription Factors
Luciferases
Mitogen-Activated Protein Kinase 7
MAP Kinase Kinase 5
Casp3 protein, mouse
Caspase 3
Caspases