Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Laboratory of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
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.
c-Jun N-末端激酶（JNK）是丝裂原活化蛋白激酶家族的成员，控制包括细胞凋亡在内的各种生理过程。JNK 的一种特定上游激活剂是丝裂原活化蛋白激酶激酶 7（MKK7）。据报道，MKK7-JNK 信号通路在神经发育中起着重要的调节作用，但在神经系统中的发育后功能尚未阐明。在这项研究中，我们生成了神经元特异性的 Mkk7 敲除小鼠（MKK7 cKO），该小鼠破坏了神经系统中 JNK 的组成性激活。MKK7 cKO 小鼠表现出昼夜行为节律受损和运动活性降低。8 月龄的 MKK7 cKO 小鼠表现出运动功能障碍，如后肢无力和步态异常，呈年龄依赖性。还观察到脊髓和肌肉的轴突变性，以及 MKK7 cKO 小鼠的大脑和脊髓中 JNK 相互作用蛋白 1 和淀粉样β前体蛋白的积累。因此，MKK7-JNK 信号通路在调节成年神经系统中的昼夜节律和神经元维持方面起着重要作用。
