DISC1 regulates the transport of the NUDEL/LIS1/14-3-3ε complex through Kinesin-1
DISC1 regulates the transport of the NUDEL/LIS1/14-3-3ε complex through Kinesin-1
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DOI：
10.1523/jneurosci.3826-06.2006
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发表时间：
2007-01-03
影响因子：
5.3
通讯作者：
Kaibuchi, Kozo
中科院分区：
文献类型：
--
作者：
Taya, Shinichiro;Shinoda, Tomoyasu;Kaibuchi, Kozo
DISC 1基因是精神分裂症易感性的候选基因。据报道DISC 1与NudE样（NUDEL）相互作用，后者与无脑畸形-1（LIS 1）和14-3-3 β形成复合物。14-3-3 β 1参与NUDEL和LIS 1在轴突中的适当定位。虽然该复合物在神经元发育中的功能意义已被报道，但该复合物进入轴突的转运机制及其在轴突形成中的功能仍然基本上未知。在这里，我们报告，驱动蛋白-1，一个马达蛋白的顺行轴突运输，被确定为一种新的DISC 1相互作用分子。DISC 1直接与Kinesin-1的重链相互作用。Kinesin-1通过DISC 1与NUDEL/LIS 1/14-3-3复合体相互作用，主要定位于细胞体，部分定位于轴突远端。DISC 1与驱动蛋白家族成员5A、NUDEL、LIS 1和14-3-3 β在生长锥中部分共定位。通过RNA干扰或显性负性形式的DISC 1的敲低抑制NUDEL、LIS 1和14-3-3 β在轴突和轴突伸长处的积累。Kinesin-1的敲低或显性负性形式抑制DISC 1在轴突和轴突伸长处的积累。此外，NUDEL或LIS 1的敲低抑制轴突伸长。总之，这些结果表明，DISC 1调节NUDEL/LIS 1/14-3-3 β复合物作为轴突伸长的货物受体定位到轴突中。
Disrupted-In-Schizophrenia 1 (DISC1) is a candidate gene for susceptibility to schizophrenia. DISC1 is reported to interact with NudE-like (NUDEL), which forms a complex with lissencephaly-1 (LIS1) and 14-3-3 epsilon. 14-3-3 epsilon is involved in the proper localization of NUDEL and LIS1 in axons. Although the functional significance of this complex in neuronal development has been reported, the transport mechanism of the complex into axons and their functions in axon formation remain essentially unknown. Here we report that Kinesin-1, a motor protein of anterograde axonal transport, was identified as a novel DISC1-interacting molecule. DISC1 directly interacted with kinesin heavy chain of Kinesin-1. Kinesin-1 interacted with the NUDEL/LIS1/14-3-3 epsilon complex through DISC1, and these molecules localized mainly at cell bodies and partially in the distal part of the axons. DISC1 partially colocalized with Kinesin family member 5A, NUDEL, LIS1, and 14-3-3 epsilon in the growth cones. The knockdown of DISC1 by RNA interference or the dominant-negative form of DISC1 inhibited the accumulation of NUDEL, LIS1, and 14-3-3 epsilon at the axons and axon elongation. The knockdown or the dominant-negative form of Kinesin-1 inhibited the accumulation of DISC1 at the axons and axon elongation. Furthermore, the knockdown of NUDEL or LIS1 inhibited axon elongation. Together, these results indicate that DISC1 regulates the localization of NUDEL/LIS1/14-3-3 epsilon complex into the axons as a cargo receptor for axon elongation.