Age-dependent motor dysfunction due to neuron-specific disruption of stress-activated protein kinase MKK7.
Age-dependent motor dysfunction due to neuron-specific disruption of stress-activated protein kinase MKK7.
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DOI：
10.1038/s41598-017-07845-x
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发表时间：
2017-08-04
影响因子：
4.6
通讯作者：
Nishina H
中科院分区：
文献类型：
--
作者：
Yamasaki T;Deki-Arima N;Kaneko A;Miyamura N;Iwatsuki M;Matsuoka M;Fujimori-Tonou N;Okamoto-Uchida Y;Hirayama J;Marth JD;Yamanashi Y;Kawasaki H;Yamanaka K;Penninger JM;Shibata S;Nishina H
C-Jun氨基末端激酶(JNK)是丝裂原活化蛋白激酶家族的一员，控制着包括细胞凋亡在内的多种生理过程。JNKs的一个特定上游激活物是丝裂原活化蛋白激酶7(MKK7)。已有报道MKK7-JNK信号在神经发育中起着重要的调节作用，但神经系统发育后功能尚未阐明。在这项研究中，我们产生了神经元特异性的MKK7基因敲除小鼠(MKK7 CKO)，它削弱了神经系统中JNK的结构性激活。MKK7 CKO小鼠表现出昼夜行为节律受损，运动能力下降。8个月龄的MKK7 CKO小鼠出现后肢无力、步态异常等运动功能障碍，且呈年龄依赖性。MKK7 CKO小鼠脊髓轴突变性和肌肉萎缩，以及轴突运输蛋白JNK相互作用蛋白1和淀粉样β前体蛋白在脑和脊髓中积聚。因此，MKK7-JNK信号通路在调节成年神经系统的昼夜节律和神经元维持方面发挥着重要作用。
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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影响因子：
5.3
作者：
Komulainen E;Zdrojewska J;Freemantle E;Mohammad H;Kulesskaya N;Deshpande P;Marchisella F;Mysore R;Hollos P;Michelsen KA;Mågard M;Rauvala H;James P;Coffey ET
通讯作者：
Coffey ET
影响因子：
4.8
作者：
Enslen, H;Raingeaud, J;Davis, RJ
通讯作者：
Davis, RJ
影响因子：
5.3
作者：
Björkblom, B;Östman, N;Coffey, ET
通讯作者：
Coffey, ET
影响因子：
4.7
作者：
Chen, JT;Lu, DH;Xiao, ZC
通讯作者：
Xiao, ZC
DOI：
10.1083/jcb.201302078
发表时间：
2013-08-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fu MM;Holzbaur EL
通讯作者：
Holzbaur EL