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

Mary Muhia,Michaela Schweizer,Edda Thies,Dorthe Labonté,Kira V Gromova,Irm Hermans-Borgmeyer,Jürgen R Schwarz,Dietmar Kuhl,Ora Ohana,Erika L.F Holzbaur,Corinna Lappe-Siefke,Francesca Xompero,Amy E Ghiretti,Matthias Kneussel

doi:10.1016/j.celrep.2016.03.086

Abstract

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 functions. Here, we generated Kif21b knockout mice and used cellular assays to investigate the relevance of KIF21B in neuronal and invivo function. We show that KIF21B is a processive motor protein and identify an additional role for KIF21B in regulating microtubule dynamics. In neurons lacking KIF21B, microtubules grow moreslowly 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. Our study provides insight into the cellular function of KIF21B and the basis for cognitive decline resulting from KIF21B dysregulation.

Highlights

Kinesin superfamily proteins (KIFs) share a common ATP-binding ‘‘motor’’ domain, fused to divergent tail domains that specify intracellular localization and function
We identify a neuronal role for KIF21B in dendritic tree branching and spine formation and show that KIF21B is necessary for learning and memory
Generation and Verification of Kif21b Knockout Mice To investigate the in vivo relevance of KIF21B, we generated Kif21b knockout (À/À) mice (Figure 1A) using knockout first embryonic stem (ES) cells obtained from the Knockout Mouse Project repository (KOMP, clone no. 24702)

Summary

Introduction

Kinesin superfamily proteins (KIFs) share a common ATP-binding ‘‘motor’’ domain, fused to divergent tail domains that specify intracellular localization and function. Kinesin-4 and -8 family members adopt dual roles as cargo translocators and regulators of MT dynamics (Drummond, 2011; Walczak et al, 2013). These findings highlight a kinesin-MT interplay in mediating intracellular cargo transport (Hirokawa et al, 2009). The plus ends of cellular MTs can dynamically remodel through stochastic length fluctuations These events, termed as dynamic instability, comprise periods of persistent MT growth interrupted by occasional rapid shrinkage: switching between these states of growth and shortening is termed catastrophe and rescue (Gardner et al, 2013)

Results

Discussion

Conclusion