Takano Tetsuya, Urushibara Tomoki, Yoshioka Nozomu, Saito Taro, Fukuda Mitsunori, Tomomura Mineko, Hisanaga Shin-Ichi
Department of Biological Sciences, Tokyo Metropolitan University, Tokyo 192-0397, Japan
Department of Biological Sciences, Tokyo Metropolitan University, Tokyo 192-0397, Japan.
Mol Biol Cell. 2014 Jun;25(11):1755-68. doi: 10.1091/mbc.E14-01-0675. Epub 2014 Mar 26.
Neurons extend two types of neurites-axons and dendrites-that differ in structure and function. Although it is well understood that the cytoskeleton plays a pivotal role in neurite differentiation and extension, the mechanisms by which membrane components are supplied to growing axons or dendrites is largely unknown. We previously reported that the membrane supply to axons is regulated by lemur kinase 1 (LMTK1) through Rab11A-positive endosomes. Here we investigate the role of LMTK1 in dendrite formation. Down-regulation of LMTK1 increases dendrite growth and branching of cerebral cortical neurons in vitro and in vivo. LMTK1 knockout significantly enhances the prevalence, velocity, and run length of anterograde movement of Rab11A-positive endosomes to levels similar to those expressing constitutively active Rab11A-Q70L. Rab11A-positive endosome dynamics also increases in the cell body and growth cone of LMTK1-deficient neurons. Moreover, a nonphosphorylatable LMTK1 mutant (Ser34Ala, a Cdk5 phosphorylation site) dramatically promotes dendrite growth. Thus LMTK1 negatively controls dendritic formation by regulating Rab11A-positive endosomal trafficking in a Cdk5-dependent manner, indicating the Cdk5-LMTK1-Rab11A pathway as a regulatory mechanism of dendrite development as well as axon outgrowth.
神经元会延伸出两种神经突——轴突和树突，它们在结构和功能上存在差异。尽管人们已经充分了解细胞骨架在神经突分化和延伸中起着关键作用，但膜成分供应给生长中的轴突或树突的机制在很大程度上仍不清楚。我们之前报道过，轴突的膜供应由狐猴激酶1（LMTK1）通过Rab11A阳性内体进行调控。在此，我们研究LMTK1在树突形成中的作用。在体外和体内，LMTK1的下调都会增加大脑皮质神经元的树突生长和分支。LMTK1基因敲除显著提高了Rab11A阳性内体顺行运动的发生率、速度和运行长度，使其达到与表达组成型活性Rab11A-Q70L的水平相似。在LMTK1缺陷神经元的细胞体和生长锥中，Rab11A阳性内体的动力学也有所增加。此外，一种不可磷酸化的LMTK1突变体（Ser34Ala，一个Cdk5磷酸化位点）显著促进树突生长。因此，LMTK1通过以Cdk5依赖的方式调节Rab11A阳性内体运输来负向控制树突形成，这表明Cdk5-LMTK1-Rab11A途径是树突发育以及轴突生长的一种调节机制。
