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Mice lacking both mixed-lineage kinase genes Mlk1 and Mlk2 retain a wild type phenotype
Nicolas Bisson1, Michel Tremblay, Fiona Robinson
1Cancer Research Centre and Department of Medical Biology, Laval University, Québec, Québec, Canada.
Abstract:
The mitogen-activated protein kinase kinase kinases of the mixed-lineage kinase (MLK) family have been shown to activate the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway, and to regulate the other two principal MAPK cascades, p38 and extracellular signal-regulated kinase (ERK). Although there is growing evidence for their involvement in neuronal cell death leading to neurodegenerative disorders, little in vivo data is available for the members of this family of kinases. Here, we report that the inactivation of mouse Mlk1 and Mlk2 genes. Mlk1(-/-) and Mlk2(-/-) mice were found to be viable and healthy. Surprisingly, mice carrying the compound Mlk1/Mlk2 null mutations were also found to be viable, fertile and to have a normal life span. The nervous system, testis and kidney, the major sites of MLK1 and 2 expression, all appear normal, as do other organs where these kinases were found to be more weakly expressed. Surprisingly, developmental neuronal programmed cell death, another potential target for MLK family members, was also found to be unaffected. Our results suggest that there is extensive functional redundancy between MLK1/MLK2 and the other member of the family, MLK3, which is also not required for survival in mouse.
Insights
Mixed-lineage kinase (MLK) family members MLK1 and MLK2 are not essential for mouse survival or development. Their inactivation, even combined, did not affect lifespan or neuronal programmed cell death, suggesting functional redundancy.
Area of Science:
- Molecular Biology
- Cell Signaling
- Neuroscience
Background:
- Mitogen-activated protein kinase kinase kinases (MAPKKKs) of the mixed-lineage kinase (MLK) family regulate key MAPK pathways (JNK, p38, ERK).
- MLK family involvement in neurodegenerative disorders is suggested, but in vivo data is limited.
Purpose of the Study:
- To investigate the in vivo function of MLK1 and MLK2 in mice.
- To determine the necessity of MLK1 and MLK2 for mouse viability, development, and lifespan.
Main Methods:
- Generation and analysis of Mlk1 and Mlk2 knockout mice, including compound Mlk1/Mlk2 null mutations.
- Assessment of mouse viability, fertility, lifespan, and organ morphology (nervous system, testis, kidney).
- Evaluation of developmental neuronal programmed cell death.
Main Results:
- Mlk1(-/-) and Mlk2(-/-) mice were viable and healthy.
- Compound Mlk1/Mlk2 null mutant mice were viable, fertile, and had normal lifespans.
- Nervous system, reproductive organs, kidneys, and other tissues appeared normal; developmental neuronal cell death was unaffected.
Conclusions:
- MLK1 and MLK2 are dispensable for mouse survival and normal development.
- Extensive functional redundancy exists between MLK1/MLK2 and MLK3, another family member.
- MLK family kinases are not essential for survival in mice, challenging their proposed roles in neurodegeneration based on in vitro data.
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