The Kinesin KIF21B Regulates Microtubule Dynamics and Is Essential for Neuronal Morphology, Synapse Function, and Learning and Memory

Abstract

SUMMARY The kinesin KIF21B is implicated in several human neurological disorders including delayed cognitive development, yet it remains unclear how KIF21B dysfunction may contribute to pathology. One limitation is that relatively little is known about KIF21B-mediated physiological mechanisms. Here, we generated Kif21b knockout mice and used cellular assays to investigate the relevance of KIF21B in neuronal and in vivo function. We show that KIF21B is a processive motor, and identify an additional role for KIF21B in regulating microtubule dynamics. In neurons lacking KIF21B, microtubules grow more slowly and persistently, leading to tighter packing in dendrites. KIF21B-deficient neurons exhibit decreased dendritic arbor complexity and reduced spine density, which correlate with deficits in synaptic transmission. Consistent with these observations, KIF21B-null mice exhibit behavioral changes involving learning and memory deficits. Collectively, our study provides insight into the cellular function of KIF21B and the basis for cognitive decline resulting from KIF21B dysregulation.

Activity-Dependent Regulation of Distinct Transport and Cytoskeletal Remodeling Functions of the Dendritic Kinesin KIF21B

“…The functional mapping of KIF21B-dependent regulation of microtubule dynamicity to the tethering activity of its C-terminus is a unique mechanism of action for a kinesin family member, and is consistent with a recent report on the KIF21B knockout mouse, which showed that the motor domain of KIF21B was not sufficient to rescue certain loss-of-function phenotypes (Muhia et al, 2016). While both kinesin-8s and kinesin-13s also bind microtubules outside of their canonical motor domains, these kinesins still require ATP hydrolysis to affect microtubule dynamics.…”

“…Only recently have cargoes of KIF21B-dependent transport begun to be identified in neurons (Labonte et al, 2013; Muhia et al, 2016). To identify potential KIF21B dendritic cargoes, we screened a number of candidates for transport defects in 10 DIV cultured hippocampal neurons in which KIF21B was depleted via RNAi.…”

“…We generated primary hippocampal cultures and acute hippocampal slices from wild-type (+/+) and KIF21B knockout (−/−) mice (Muhia et al, 2016) and examined the levels of BDNF-induced S133 phosphorylation of the nuclear transcription factor CREB as a readout for efficient transport of BDNF/TrkB signaling complexes to the nucleus (Finkbeiner et al, 1997; Pizzorusso et al, 2000). We observed robust induction of CREB S133 phosphorylation following BDNF treatment of wild-type cultures and slices, but strikingly, these effects were abolished in KIF21B knockouts (Figure 4I,J).…”

“…KIF21A is restricted to the axon, and KIF21B localizes to both axons and dendrites (Jenkins et al, 2012; Marszalek et al, 1999), making it one of only a few kinesins to exhibit significant dendritic localization (Huang and Banker, 2012; Setou et al, 2002). The recent characterization of the KIF21B knockout mouse highlights the importance of this kinesin, as KIF21B −/− neurons exhibit decreased dendritic branching and spine density, coupled with a reduction in surface expression of synaptic receptors (Muhia et al, 2016). These cellular deficits are reflected functionally in learning and memory deficits.…”

“…These cellular deficits are reflected functionally in learning and memory deficits. While KIF21B has been reported to act as both a canonical kinesin motor and a regulator of microtubule dynamics (Labonte et al, 2013; Muhia et al, 2016), a mechanistic understanding of how KIF21B regulates these processes to affect neuronal function remains unknown.…”