Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan.
J Biol Chem. 2010 Dec 24;285(52):40554-61. doi: 10.1074/jbc.M110.179481. Epub 2010 Oct 18.
Centrosomes play a crucial role in the directed migration of developing neurons. However, the underlying mechanism is poorly understood. This study has identified a novel disrupted in schizophrenia 1 (DISC1)-interacting protein, named CAMDI after coiled-coil protein associated with myosin II and DISC1, which translocates to the centrosome in a DISC1-dependent manner. Knockdown of CAMDI by shRNA revealed severely impaired radial migration with disoriented centrosomes. A yeast two-hybrid screen identified myosin II as a binding protein of CAMDI. CAMDI interacts preferentially with phosphomyosin II and induces an accumulation of phosphomyosin II at the centrosome in a DISC1-dependent manner. Interestingly, one single nucleotide polymorphism of the CAMDI gene (R828W) is identified, and its gene product was found to reduce the binding ability to phosphomyosin II. Furthermore, mice with overexpression of R828W in neurons exhibit an impaired radial migration. Our findings indicate that CAMDI is required for radial migration probably through DISC1 and myosin II-mediated centrosome positioning during neuronal development.
中心体在发育神经元的定向迁移中起着至关重要的作用。然而，其潜在的机制还不清楚。本研究鉴定了一种新的分裂症相关蛋白 1（DISC1）相互作用蛋白，命名为 CAMDI，因其与肌球蛋白 II 和 DISC1 相关的卷曲螺旋蛋白而得名，该蛋白以依赖于 DISC1 的方式向中心体移位。通过 shRNA 敲低 CAMDI 会导致放射状迁移严重受损，中心体定向紊乱。酵母双杂交筛选鉴定出肌球蛋白 II 是 CAMDI 的结合蛋白。CAMDI 优先与磷酸化肌球蛋白 II 相互作用，并以依赖于 DISC1 的方式诱导磷酸化肌球蛋白 II 在中心体的积累。有趣的是，CAMDI 基因（R828W）存在一个单核苷酸多态性，其基因产物被发现降低了与磷酸化肌球蛋白 II 的结合能力。此外，神经元中过表达 R828W 的小鼠表现出放射状迁移受损。我们的研究结果表明，CAMDI 可能通过 DISC1 和肌球蛋白 II 介导的中心体定位在神经元发育过程中对放射状迁移是必需的。
