WD14-1
Teneurin-4 Mediates Oligodendrocyte-Axon Interaction and Regulates Myelination
細胞接着分子Teneurin-4を介したオリゴデンドロサイト-軸索間相互作用による髄鞘形成の制御
Hayashi Chikako（林 千香子），鈴木 喜晴，木倉 直美，細田 ゆき奈，馬渕 洋，赤澤 智宏
Graduate School of Medical and Dental Sciences, TMDU, Tokyo, Japan
Oligodendrocytes (OLs), myelinating cells in the central nervous system (CNS), contribute to formation of precise neural networks. The interaction of OLs with axons is essential for myelination. Our previous study revealed that Teneurin-4 (Ten-4), a type II transmembrane protein, was a key regulator of myelination in the CNS. Ten-4 was expressed on oligodendrocyte precursor cells (OPCs)/OLs, and depletion of Ten-4 caused hypomyelination and tremors. However, molecular mechanisms of Ten-4 function have not been well elucidated. Here we show that crucial roles of Ten-4 on OPCs/OLs in myelination. Our in vivo analysis demonstrated that defects in initial contacts of OLs with axons and in OLs process extension were observed in Ten-4 deficient mice. Furthermore, these mice displayed the reduction of actin assembly in the cytoplasm of myelin. From the above, Ten-4 was required for the initial steps of myelination, probably through the interaction with axons. Hence, we next explored the binding partners of Ten-4 for the OL-axon interaction, and as a result, Ten isoforms (Ten-1 to -4) were selected as candidates. First, we found that all Ten isoforms had homophilic and heterophilic cell-cell adhesion activity. In addition, OPCs/OLs attached to the recombinant extracellular domains of Ten-1 to -4 (rTen-1 to -4ECD), and especially rTen-1, -3, and -4ECD showed high attachment activity of OPCs/OLs. The attachment activity was inhibited in the presence of soluble rTen-4ECD. Finally, to examine the effect of binding of Ten-4 with Ten isoforms, we cultured OPCs/OLs on rTen-1 to -4ECD and found promoted OL process formation with actin assembly. These results revealed that Ten-4 plays a crucial role in cell adhesion and cytoskeletal organization in oligodendrocytes for CNS myelination. | | WD14-2
Regulation of nuclear translocation of the SRF transcriptional coactivator MKL2 by membrane depolarization
神経細胞の脱分極による転写活性化因子MKL2の核移行制御
Tanabe Hiroki（田邉 広樹）1，佐野 友香里1，加藤 真之佑1，今西 詩織1，阪上 洋行2，伊原 大輔1，田渕 明子1
1Lab. of Mol. Neurobio., Grad. Sch. of Med & Pharm.
2Dept. Anat., Sch. of Med., Kitasato. Univ.
Construction of neural networks and changes in synaptic morphology and function plays fundamental roles in higher brain functions such as learning and memory. Control of these physiological processes is mediated by gene expression. Thus, in the past decades, molecular mechanisms of neuronal activity-dependent gene expression have been elucidated. Especially, transcription factor CREB and its coactivator CRTC1 are thought to be main players in brain function for a long time. Although another transcription factor SRF is involved in brain development, regulation of SRF coactivator megakaryoblastic leukemia (MKL) in neurons remains unresolved. In this study, we have focused on MKL2, which is highly expressed in the forebrain, and investigated whether or not MKL2 translocates into a nucleus by stimulation of cultured cortical neurons. Brain-derived neurotrophic factor (BDNF) did not cause nuclear translocation of MKL2. However, membrane depolarization by high KCl drastically and transiently induced nuclear translocation of MKL2. The retention time of nuclear MKL2 was very short (30 min) and MKL2 went back to the cytoplasm 60 min after stimulation. Administration of the blocker for NMDA receptor or L-type calcium channel inhibited the nuclear translocation of MKL2, indicating that Ca2+ influx through these channels is critical for nuclear translocation of MKL2. Our previous study demonstrated that MKL2 was localized at synapses. Taken together, our findings indicate that the synapse to nucleus signaling induced by membrane depolarization induces the nuclear translocation of MKL2 in neurons. These findings provide new insight into understanding neuronal activity-dependent gene expression. |
