Mechanisms of dendritic cargo trafficking and microtubule dynamic regulation by KIF21B

 描述（由申请人提供）：神经元是高度极化的细胞，延伸专门用于发送（轴突）和接收（树突）信息的不同过程。正确的蛋白质货物的准确运输到轴突或树突隔室是保持这种极性，从而保持适当的神经元功能所必需的。这一过程受沿微管细胞骨架沿着移动的动力蛋白和驱动蛋白运动蛋白的调节。重要的是，蛋白质货物的错误定位或微管和运动蛋白的功能障碍涉及许多神经系统疾病，包括神经发育障碍，如精神发育迟滞和自闭症。由于轴突微管的极性一致，轴突运输得到了很好的研究，而树突微管的结构更为复杂;因此，介导树突运输的马达以及树突微管本身的动力学在很大程度上仍然未知。驱动蛋白-4家族的几个成员已经成为许多神经系统疾病的疾病位点，包括KIF 4A（精神发育迟滞），KIF 21 A（CFEOM 1）和KIF 21 B（多发性硬化症）。有趣的是，密切相关的驱动蛋白-4家族成员KIF 21 A和KIF 21 B显示不同的亚细胞定位模式，尽管它们的序列同源性。虽然KIF 21 A优先运输到轴突，但KIF 21 B也定位于树突。基于序列分析和初步数据，我们假设KIF 21 B在树突中起着双重作用，作为分子马达和动态微管重塑的调节剂。在这项提议中，我们将使用单分子测定和啮齿动物海马神经元的实时成像来充分表征KIF 21 B在树突中的功能。我们对KIF 21 B的研究将有助于我们理解树突状驱动蛋白的全部功能 促进树突和轴突室的功能规范，并阐明很少研究但必不可少的树突运输过程，这对我们开发有效治疗神经发育障碍的能力至关重要。

 DESCRIPTION (provided by applicant): Neurons are highly polarized cells, extending distinct processes specialized to send (axons) and receive (dendrites) information. The accurate trafficking of the correct protein cargoes to either the axonal or dendritic compartments is required to maintain this polarity and therefore proper neuronal function. This process is regulated by dynein and kinesin motor proteins that move along the microtubule cytoskeleton. Importantly, the mislocalization of protein cargos or dysfunction of microtubule and motor proteins is implicated in a number of neurological disorders, including neurodevelopmental disorders such as mental retardation and autism. While axonal trafficking is well studied due to the uniform polarity of axonal microtubules, dendritic microtubule structure is more complex; thus, the motors that mediate dendritic trafficking as well as the dynamics of dendritic microtubules themselves remain largely unknown. Several members of the kinesin-4 family have emerged as disease loci for a number of neurological disorders, including KIF4A (mental retardation), KIF21A (CFEOM1), and KIF21B (multiple sclerosis). Intriguingly, the closely related kinesin-4 family members KIF21A and KIF21B display distinct subcellular localization patterns despite their sequence homology. While KIF21A is preferentially trafficked to axons, KIF21B localizes to dendrites as well. Based on sequence gazing and preliminary data, we hypothesize that KIF21B plays a dual role in dendrites as a molecular motor and a regulator of dynamic microtubule remodeling. In this proposal, we will use single molecule assays and live imaging in rodent hippocampal neurons to fully characterize the function of KIF21B in dendrites. Our studies of KIF21B will help us to understand how the full repertoire of dendritic kinesins function to promote the functional specification of the dendritic and axonal compartments, and shed light on the little studied but essential process of dendritic trafficking, knowledge which is essential for our ability to develop effective therapeutics for neurodevelopmental disorders.