Mitotic Motor KIFC1 Is an Organizer of Microtubules in the Axon

Abstract

KIFC1 (also called HSET or kinesin-14a) is best known as a multifunctional motor protein essential for mitosis. The present studies are the first to explore KIFC1 in terminally postmitotic neurons. Using RNA interference to partially deplete KIFC1 from rat neurons (from animals of either gender) in culture, pharmacologic agents that inhibit KIFC1, and expression of mutant KIFC1 constructs, we demonstrate critical roles for KIFC1 in regulating axonal growth and retraction as well as growth cone morphology. Experimental manipulations of KIFC1 elicit morphological changes in the axon as well as changes in the organization, distribution, and polarity orientation of its microtubules. Together, the results indicate a mechanism by which KIFC1 binds to microtubules in the axon and slides them into alignment in an ATP-dependent fashion and then cross-links them in an ATP-independent fashion to oppose their subsequent sliding by other motors.Here, we establish that KIFC1, a molecular motor well characterized in mitosis, is robustly expressed in neurons, where it has profound influence on the organization of microtubules in a number of different functional contexts. KIFC1 may help answer long-standing questions in cellular neuroscience such as, mechanistically, how growth cones stall and how axonal microtubules resist forces that would otherwise cause the axon to retract. Knowledge about KIFC1 may help researchers to devise strategies for treating disorders of the nervous system involving axonal retraction given that KIFC1 is expressed in adult neurons as well as developing neurons.

Double Duty: Mitotic Kinesins and Their Post-Mitotic Functions in Neurons

“…KIF1C is a minus-end-directed motor that is evolutionarily conserved from simple yeasts to higher eukaryotes [ 26 ]. Apart from its function in development, KIF1C is highly expressed in the CNS throughout adulthood [ 48 , 59 ], indicating that it may function in post-mitotic neurons. Work from Muralidharan et al shows that KIF1C plays a vital role in the organization of microtubules in developing axons [ 48 ].…”

“…Apart from its function in development, KIF1C is highly expressed in the CNS throughout adulthood [ 48 , 59 ], indicating that it may function in post-mitotic neurons. Work from Muralidharan et al shows that KIF1C plays a vital role in the organization of microtubules in developing axons [ 48 ]. For instance, depletion or pharmacological inhibition of KIF1C in rat embryonic hippocampal neurons resulted in shorter axons in addition to reduced secondary and tertiary branching [ 48 ].…”

“…Work from Muralidharan et al shows that KIF1C plays a vital role in the organization of microtubules in developing axons [ 48 ]. For instance, depletion or pharmacological inhibition of KIF1C in rat embryonic hippocampal neurons resulted in shorter axons in addition to reduced secondary and tertiary branching [ 48 ]. Axonal growth was also impaired, as KIF1C depleted axons of rat spinal cord ganglion (SCG) neurons grew in spurts with periods of stalled growth [ 48 ].…”

“…For instance, depletion or pharmacological inhibition of KIF1C in rat embryonic hippocampal neurons resulted in shorter axons in addition to reduced secondary and tertiary branching [ 48 ]. Axonal growth was also impaired, as KIF1C depleted axons of rat spinal cord ganglion (SCG) neurons grew in spurts with periods of stalled growth [ 48 ]. This contrasts with the control group that grew steadily.…”

“…The growth cones of the axons were also altered with KIF1C depletion. KIF1C depleted neurons had smaller growth cones with fewer filopodia occupied by microtubules compared to controls [ 48 ]. Furthermore, the tips of KIF1C axons were blunted and clubbed in comparison to the control, which were fan-like in nature [ 48 ].…”