Investigating a neuronal Kinesin-Myosin Interaction in Dendritic Spines underlying Synaptic Structure and Function

动蛋白马达蛋白介导分子货物沿富含神经元胞体、轴突和树突的微管进行长距离运输。同样，肌球蛋白沿着肌动蛋白细丝运输分子，肌动蛋白细丝在细胞皮质和树突中含量非常丰富。这两个细胞骨架运输系统在很大程度上是独立发挥作用的，但微管偶尔会以突触活动依赖的方式侵入富含肌动蛋白的脊柱突起。拟议的项目是基于一项意想不到的发现，即KIF21B与神经元中的肌球蛋白Va发生物理作用。由于动蛋白-肌球蛋白在哺乳动物中的相互作用还没有报道，我们的目标是研究这两个马达在中枢神经元中的功能关系。我们的初步数据表明，肌球蛋白Va携带KIF21B进入树突棘，而KIF21B对肌球蛋白的定位并不重要。值得注意的是，来自KIF21B基因敲除小鼠的神经元显示出明显更大的脊椎和更稳定的肌动蛋白细胞骨架。由于KIF21B和肌球蛋白Va介导NMDA型和AMPA型谷氨酸受体的传递或循环，我建议从突触结构和功能方面研究这种新的相互作用。我建议了三个工作包来研究Kinesin-Myosin相互作用对I。微管侵入脊椎，II.)突触蛋白的传递和再循环。突触功能和可塑性。研究神经元脊椎结构上的动蛋白-肌球蛋白相互作用可以为微管和肌动蛋白依赖的运输过程的功能相互作用提供新的基本见解。

Kinesin motor proteins mediate long distance transport of molecular cargoes along microtubules that are enriched in neuronal somata, axons and dendrites. Likewise, myosins transport molecules along actin filaments, which are highly abundant underneath the cellular cortex and in dendritic spines. Both cytoskeletal transport systems act largely independent, however microtubules occasionally invade into actin-rich spine protrusions in a synaptic activity-dependent manner.The proposed project is based on the unexpected finding that the kinesin KIF21B physically interacts with myosin Va in neurons. Since Kinesin-Myosin interactions have not been reported in mammals, we aim to investigate the functional relationship of both motors in central neurons.Our preliminary data suggest that myosin Va piggybacks KIF21B into dendritic spines, whereas KIF21B is not important to localize the myosin. Notably, neurons derived from a KIF21B genetic knockout mouse display significantly larger spines and a more stable actin cytoskeleton.Since KIF21B and myosin Va mediate the delivery or recycling of NMDA- and AMPA-type glutamate receptors, I propose to study this novel interaction with respect to synaptic structure and function. I suggest three work packages to investigate the functional relevance of the kinesin-myosin interaction for i.) the invasion of microtubules into spines, ii.) the delivery and recycling of synaptic proteins and iii.) synaptic function and plasticity.Investigating kinesin-myosin interactions at neuronal spine structures can shed new fundamental insights into the functional interplay of microtubule- and actin-dependent transport processes.