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.
The proper function of the central nervous system (CNS) depends on the correct localization of cargoes such as proteins and organelles to distinct locations within a given neuron. A hallmark of many neurodevelopmental and neurodegenerative disorders is the misregulation of protein trafficking in dendrites, which are where a neuron receives most of its input from other neurons. I will characterize the function of KIF21B, a relatively little-studied motor protein that carries cargoes to dendrites, to provide a window through which to study dendritic trafficking as a whole and its misregulation in neurological disease.
| Ayloo, Swathi; Guedes-Dias, Pedro; Ghiretti, Amy E et al. (2017) Dynein efficiently navigates the dendritic cytoskeleton to drive the retrograde trafficking of BDNF/TrkB signaling endosomes. Mol Biol Cell 28:2543-2554 |
| Ghiretti, Amy E; Thies, Edda; Tokito, Mariko K et al. (2016) Activity-Dependent Regulation of Distinct Transport and Cytoskeletal Remodeling Functions of the Dendritic Kinesin KIF21B. Neuron 92:857-872 |
| Nirschl, Jeffrey J; Ghiretti, Amy E; Holzbaur, Erika L F (2016) Lipid Rafts Assemble Dynein Ensembles. Trends Biochem Sci 41:393-394 |
