Mice lacking both mixed-lineage kinase genes Mlk1 and Mlk2 retain a wild type phenotype

Cell Cycle. 2008 Apr 1;7(7):909-16. doi: 10.4161/cc.7.7.5610. Epub 2008 Jan 11.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Blotting, Western
  • DNA Primers / genetics
  • Gastric Mucosa / metabolism
  • Gene Silencing
  • MAP Kinase Kinase Kinases / deficiency*
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / growth & development
  • Muscle, Skeletal / metabolism
  • Neurons / cytology
  • Phenotype*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spleen / growth & development
  • Spleen / metabolism
  • Stomach / growth & development
  • Superior Cervical Ganglion / metabolism


  • DNA Primers
  • MAP Kinase Kinase Kinases
  • Map3k10 protein, mouse
  • Map3k9 protein, mouse