TY - JOUR
T1 - Age-dependent motor dysfunction due to neuron-specific disruption of stress-Activated protein kinase MKK7
AU - Yamasaki, Tokiwa
AU - Deki-Arima, Norie
AU - Kaneko, Asahito
AU - Miyamura, Norio
AU - Iwatsuki, Mamiko
AU - Matsuoka, Masato
AU - Fujimori-Tonou, Noriko
AU - Okamoto-Uchida, Yoshimi
AU - Hirayama, Jun
AU - Marth, Jamey D.
AU - Yamanashi, Yuji
AU - Kawasaki, Hiroshi
AU - Yamanaka, Koji
AU - Penninger, Josef M.
AU - Shibata, Shigenobu
AU - Nishina, Hiroshi
N1 - Funding Information:
This work is supported by a Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research 26293012
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41598-017-07845-x
DO - 10.1038/s41598-017-07845-x
M3 - Article
C2 - 28779160
AN - SCOPUS:85026821210
SN - 2045-2322
VL - 7
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 7348
ER -