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

Abstract

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.

A mouse model of DEPDC5-related epilepsy: Neuronal loss of Depdc5 causes dysplastic and ectopic neurons, increased mTOR signaling, and seizure susceptibility

“…We also observed enlarged, strongly pS6-positive neurons in other brain regions including the thalamus and amygdala (Supplemental Fig. 1), but not in the caudate and putamen due to relatively sparse Cre expression in the striatum, as previously shown (Yamasaki et al, 2017). These findings strongly indicate that Depdc5 loss in neurons throughout the majority of the brain results in mTORC1 hyperactivation.…”

Growth Cone Phosphoproteomics Reveals that GAP-43 Phosphorylated by JNK Is a Marker of Axon Growth and Regeneration

“…We also identified the upstream signal that activates JNK. In the brain, MKK7 is a specific activator of JNK ( Yamasaki et al., 2011 ), and mice with brain-specific conditional knockout (cKO) of MKK7 exhibit hypoactive axon formation in the developing brain ( Yamasaki et al., 2011 , Yamasaki et al., 2017 ). Using our phospho-specific Abs in this cKO mouse, we found that phosphorylation signals in the brain were greatly diminished, as also observed with the chemical inhibitor ( Figure 3 C).…”

MKK7 deficiency in mature neurons impairs parental behavior in mice

“…Previously, we reported that neuron‐specific Mkk7 ‐deficient mice ( Mkk7 flox/flox Syn‐Cre mice, hereafter designated cKO mice) were born at the expected Mendelian ratio and were fertile (Yamasaki et al., 2017). During our regular maintenance of these animals, however, we noted that we rarely obtained pups from cKO female mice.…”

“…Mice homozygous for the targeted (floxed) Mkk7 allele were previously described (Schramek et al., 2011), as were neuron‐specific Cre deleter strain Synapsin‐Cre ( Syn‐Cre ) transgenic mice on a C57BL/6 background (Zhu et al., 2001). The generation of Mkk7 flox/flox Syn‐Cre mice was described in our previous report (Yamasaki et al., 2017). ROSA‐tdTomato mice on the C57BL/6 background [B6.Cg‐Gt(ROSA)26Sortm9(CAG‐tdTomato)Hze/J] were originally obtained from the Jackson laboratory (Madisen et al., 2010) and maintained at the Mouse Facility of Tokyo Medical and Dental University.…”

“…In mouse brain, Nestin‐Cre‐mediated deletion of Mkk4 or Mkk7 causes developmental defects, indicating that MKK4/7‐JNK signaling is necessary not only for stress responses but also for early development of the brain (Wang et al., 2007; Yamasaki et al., 2011). Similarly, Syn‐Cre‐dependent deletion of Mkk7 , which is neuron‐specific, impairs circadian rhythms in 10‐week‐old mice, with 8‐month‐old mutants showing an age‐dependent decrease in locomotor activity (Yamasaki et al., 2017). Thus, the MKK7‐JNK pathway regulates diverse neural functions in addition to brain development.…”