Reevaluation of the Role of Extracellular Signal-Regulated Kinase 3 in Perinatal Survival and Postnatal Growth Using New Genetically Engineered Mouse Models

ABSTRACT

The physiological functions of the atypical mitogen-activated protein kinase extracellular signal-regulated kinase 3 (ERK3) remain poorly characterized. Previous analysis of mice with a targeted insertion of the lacZ reporter in the Mapk6 locus (Mapk6^lacZ) showed that inactivation of ERK3 in Mapk6^lacZ mice leads to perinatal lethality associated with intrauterine growth restriction, defective lung maturation, and neuromuscular anomalies. To further explore the role of ERK3 in physiology and disease, we generated novel mouse models expressing a catalytically inactive (Mapk6^KD) or conditional (Mapk6^Δ) allele of ERK3. Surprisingly, we found that mice devoid of ERK3 kinase activity or expression survive the perinatal period without any observable lung or neuromuscular phenotype. ERK3 mutant mice reached adulthood, were fertile, and showed no apparent health problem. However, analysis of growth curves revealed that ERK3 kinase activity is necessary for optimal postnatal growth. To gain insight into the genetic basis underlying the discrepancy in phenotypes of different Mapk6 mutant mouse models, we analyzed the regulation of genes flanking the Mapk6 locus by quantitative PCR. We found that the expression of several Mapk6 neighboring genes is deregulated in Mapk6^lacZ mice but not in Mapk6^KD or Mapk6^Δ mutant mice. Our genetic analysis suggests that off-target effects of the targeting construct on local gene expression are responsible for the perinatal lethality phenotype of Mapk6^lacZ mutant mice.

KEYWORDS:

• ERK3
• MAP kinases
• mouse models
• protein kinases
• signal transduction

This article is related to:

Germ Line Deletion Reveals a Nonessential Role of Atypical Mitogen-Activated Protein Kinase 6/Extracellular Signal-Regulated Kinase 3

Germ Line Deletion Reveals a Nonessential Role of Atypical Mitogen-Activated Protein Kinase 6/Extracellular Signal-Regulated Kinase 3

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SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at https://doi.org/10.1128/MCB.00527-18.

ACKNOWLEDGMENTS

We thank Mélania Gombos for help with animal experimentation, Sébastien Harton for technical support in generating the Mapk6^flox mouse line, and Raphaelle Lambert for qPCR analysis.

This work was supported in part by grants from the Canadian Institutes for Health Research to S.M. S.M. held the Canada Research Chair in Cellular Signaling.

Notes

For a companion article on this topic, see https://doi.org/10.1128/MCB.00516-18.