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Glia and Glia-Neuron Interaction

開催日 2014/9/12
時間 11:00 - 12:00
会場 Poster / Exhibition(Event Hall B)

MAP kinase cascade in M-CSF-triggered microglial proliferation

  • P2-063
  • 山本 伸一 / Shinichi Yamamoto:1 高坂 新一 / Shinichi Kohsaka:2 中嶋 一行 / Kazuyuki Nakajima:1 
  • 1:創価大学工学部生命情報工学科 / Dept. of Bioinformatics, Faculty of Engineering, Soka University, Tokyo, Japan 2:国立精神・神経センター 神経研究所 / Dept. of Neurochemistry, National Institute of Neuroscience, Tokyo, Japan 

Axotomy of rat facial nerve leads to an increase of microglial cell number in the ipsilateral facial nucleus. In the previous study, we demonstrated that up-regulated macrophage-colony stimulating factor (M-CSF) in the transected facial nucleus triggers the induction of cFms (receptor for M-CSF), proliferating cell nuclear antigen (PCNA) and cell cycle-associated proteins, including cyclins, cyclin-dependent protein kinases (Cdks) and Cdk inhibitors (CdkIs) in microglia and causes the microglia to divide. The microglial proliferation was found to be regulated by the interactions among cyclin A, cyclin D, Cdk2, Cdk4 and p21, and the induction of cyclins/PCNA and cFms, which are requisite for microglial proliferation, was found to be differentially regulated by c-Jun N-terminal kinase (JNK) and p38 MAP kinase (p38) in M-CSF-stimulated microglia. However, the signaling mechanism of M-CSF-triggered microglial proliferation remains to be elucidated. In the present study, we analyzed the MAP kinase cascade in M-CSF-triggered microglial proliferation. Both JNK and p38 were phosphorylated by stimulation with M-CSF, and were significantly suppressed by pretreatment with cFms inhibitor. We also confirmed that the upstream kinases of JNK/p38 MKK4 and MKK3/6 are activated by stimulation with M-CSF. Furthermore, we demonstrated that mitogen activated protein kinase activated protein kinase-2 (MAPKAPK-2), cyclic AMP responsive element binding protein (CREB), mitogen-and stress-activated protein kinase-1 (MSK-1) and ETS family of transcription factor (ETS-1) are all activated in M-CSF stimulated microglia. These signaling molecules are thought to be located at downstream of JNK/p38 because their phosphorylations were suppressed in the presence of JNK/p38 inhibitors. Our results indicated that MAPKAPK-2, CREB, MSK-1 and ETS-1 are serving at downstream of JNK/p38 that are activated by M-CSF/cFms signaling.

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