Muhia Mary, Thies Edda, Labonté Dorthe, Ghiretti Amy E, Gromova Kira V, Xompero Francesca, Lappe-Siefke Corinna, Hermans-Borgmeyer Irm, Kuhl Dietmar, Schweizer Michaela, Ohana Ora, Schwarz Jürgen R, Holzbaur Erika L F, Kneussel Matthias
Department of Molecular Neurogenetics, University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany.
Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6085, USA.
Cell Rep. 2016 May 3;15(5):968-977. doi: 10.1016/j.celrep.2016.03.086. Epub 2016 Apr 21.
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 in vivo 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 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. Our study provides insight into the cellular function of KIF21B and the basis for cognitive decline resulting from KIF21B dysregulation.
驱动蛋白KIF21B与多种人类神经疾病有关，包括认知发育迟缓，但目前尚不清楚KIF21B功能障碍如何导致病理变化。一个限制因素是，人们对KIF21B介导的生理功能了解相对较少。在这里，我们培育了Kif21b基因敲除小鼠，并使用细胞分析方法来研究KIF21B在神经元和体内功能中的相关性。我们发现KIF21B是一种持续性运动蛋白，并确定了KIF21B在调节微管动力学方面的额外作用。在缺乏KIF21B的神经元中，微管生长更缓慢且持续时间更长，导致树突中微管堆积更紧密。缺乏KIF21B的神经元表现出树突分支复杂性降低和棘突密度减少，这与突触传递缺陷相关。与这些观察结果一致，Kif21b基因敲除小鼠表现出涉及学习和记忆缺陷的行为变化。我们的研究深入了解了KIF21B的细胞功能以及KIF21B失调导致认知衰退的基础。
