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Dev Cell. 2013 Oct 28;27(2):145-160. doi: 10.1016/j.devcel.2013.09.010. Epub 2013 Oct 10.

CFEOM1-associated kinesin KIF21A is a cortical microtubule growth inhibitor.

Author information

1
Department of Cell Biology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
2
Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
3
Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands; Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
4
Department of Neuroscience, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
5
Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands; Department of Neuroscience, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
6
Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands.
7
Kobe institute, RIKEN, Center for Developmental Biology, Optical Image Analysis Unit, Chuo-ku, Kobe 650-0047, Japan.
8
Proteomics Center, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
9
Biomolecular Research, Paul Scherrer Insitut, 5232 Villingen PSI, Switzerland.
10
Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
11
Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands; Department of Neuroscience, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands. Electronic address: c.hoogenraad@uu.nl.
12
Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands. Electronic address: a.akhmanova@uu.nl.

Abstract

Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.

PMID:
24120883
DOI:
10.1016/j.devcel.2013.09.010
[Indexed for MEDLINE]
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