Journal article
Human CFEOM1 mutations attenuate KIF21A autoinhibition and cause oculomotor axon stalling
Neuron (Cambridge, Mass.), Vol.82(2), pp.334-349
04/16/2014
DOI: 10.1016/j.neuron.2014.02.038
PMCID: PMC4002761
PMID: 24656932
Abstract
The ocular motility disorder "Congenital fibrosis of the extraocular muscles type 1" (CFEOM1) results from heterozygous mutations altering the motor and third coiled-coil stalk of the anterograde kinesin, KIF21A. We demonstrate that Kif21a knockin mice harboring the most common human mutation develop CFEOM. The developing axons of the oculomotor nerve's superior division stall in the proximal nerve; the growth cones enlarge, extend excessive filopodia, and assume random trajectories. Inferior division axons reach the orbit but branch ectopically. We establish a gain-of-function mechanism and find that human motor or stalk mutations attenuate Kif21a autoinhibition, providing in vivo evidence for mammalian kinesin autoregulation. We identify Map1b as a Kif21a-interacting protein and report that Map1b⁻/⁻ mice develop CFEOM. The interaction between Kif21a and Map1b is likely to play a critical role in the pathogenesis of CFEOM1 and highlights a selective vulnerability of the developing oculomotor nerve to perturbations of the axon cytoskeleton.
Details
- Title: Subtitle
- Human CFEOM1 mutations attenuate KIF21A autoinhibition and cause oculomotor axon stalling
- Creators
- Long Cheng - Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Program in Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USAJigar Desai - Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Program in Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USACarlos J Miranda - Program in Genomics, Boston Children's Hospital, Boston, MA 02115, USAJeremy S Duncan - Department of Biology, University of Iowa, College of Liberal Arts and Sciences, Iowa City, IA, 52242, USAWeihong Qiu - Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USAAlicia A Nugent - Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USAAdrianne L Kolpak - Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USACarrie C Wu - Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USAEugene Drokhlyansky - Program in Genomics, Boston Children's Hospital, Boston, MA 02115, USAMichelle M Delisle - Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Program in Genomics, Boston Children's Hospital, Boston, MA 02115, USAWai-Man Chan - Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Program in Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815, USAYan Wei - Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USAFriedrich Propst - Max F. Perutz Laboratories, University of Vienna, Department of Biochemistry and Cell Biology, Dr. Bohrgasse 9, A-1030 Vienna, AustriaSamara L Reck-Peterson - Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USABernd Fritzsch - Department of Biology, University of Iowa, College of Liberal Arts and Sciences, Iowa City, IA, 52242, USAElizabeth C Engle - Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Program in Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Medicine (Genetics), Boston Children's Hospital, Boston, MA 02115, USA; Department of Ophthalmology, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815, USA; The Broad Institute of Harvard and MIT, 301 Binney Street, Cambridge, MA 02142, USA. Electronic address: elizabeth.engle@childrens.harvard.edu
- Resource Type
- Journal article
- Publication Details
- Neuron (Cambridge, Mass.), Vol.82(2), pp.334-349
- DOI
- 10.1016/j.neuron.2014.02.038
- PMID
- 24656932
- PMCID
- PMC4002761
- NLM abbreviation
- Neuron
- ISSN
- 0896-6273
- eISSN
- 1097-4199
- Publisher
- United States
- Grant note
- P30 HD018655 / NICHD NIH HHS R01 EY013583 / NEI NIH HHS P30 CA06516 / NCI NIH HHS P30 CA006516 / NCI NIH HHS Howard Hughes Medical Institute P30 HD18655 / NICHD NIH HHS
- Language
- English
- Date published
- 04/16/2014
- Academic Unit
- Iowa Neuroscience Institute; Biology; Craniofacial Anomalies Research Center
- Record Identifier
- 9984070592902771
Metrics
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