Age-dependent motor dysfunction due to neuron-specific disruption of stress-activated protein kinase MKK7

Sci Rep. 2017 Aug 4;7(1):7348. doi: 10.1038/s41598-017-07845-x.


c-Jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase family and controls various physiological processes including apoptosis. A specific upstream activator of JNKs is the mitogen-activated protein kinase kinase 7 (MKK7). It has been reported that MKK7-JNK signaling plays an important regulatory role in neural development, however, post-developmental functions in the nervous system have not been elucidated. In this study, we generated neuron-specific Mkk7 knockout mice (MKK7 cKO), which impaired constitutive activation of JNK in the nervous system. MKK7 cKO mice displayed impaired circadian behavioral rhythms and decreased locomotor activity. MKK7 cKO mice at 8 months showed motor dysfunctions such as weakness of hind-limb and gait abnormality in an age-dependent manner. Axonal degeneration in the spinal cord and muscle atrophy were also observed, along with accumulation of the axonal transport proteins JNK-interacting protein 1 and amyloid beta precursor protein in the brains and spinal cords of MKK7 cKO mice. Thus, the MKK7-JNK signaling pathway plays important roles in regulating circadian rhythms and neuronal maintenance in the adult nervous system.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Brain / diagnostic imaging
  • Brain / metabolism
  • Brain / physiopathology
  • Circadian Rhythm / genetics
  • Disease Models, Animal
  • Disease Progression
  • Gene Deletion
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Kinase 7 / genetics
  • MAP Kinase Kinase 7 / metabolism*
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Mice, Transgenic
  • Motor Activity
  • Motor Disorders / diagnosis
  • Motor Disorders / etiology*
  • Motor Disorders / metabolism*
  • Neurons / metabolism*
  • Organ Specificity
  • Rats
  • Stress, Physiological*


  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 7
  • Map2k7 protein, mouse