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Published on: July 16, 2019
Human CFEOM1 mutations attenuate KIF21A autoinhibition and cause oculomotor axon stalling
Long Cheng1, Jigar Desai1, Carlos J Miranda2
1Department 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.
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.
Insights
Congenital fibrosis of the extraocular muscles type 1 (CFEOM1) is caused by KIF21A mutations. Mouse models show these mutations disrupt oculomotor nerve axon development, revealing a gain-of-function mechanism.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Congenital fibrosis of the extraocular muscles type 1 (CFEOM1) is an inherited ocular motility disorder.
- It is linked to heterozygous mutations in the KIF21A gene, which encodes a motor protein involved in axonal transport.
Purpose of the Study:
- To investigate the pathogenic mechanism of CFEOM1 by creating and analyzing a mouse model with a common human KIF21A mutation.
- To explore the role of KIF21A autoregulation and its interaction with Map1b in CFEOM1 pathogenesis.
Main Methods:
- Generated Kif21a knockin mice carrying a common human CFEOM1-associated mutation.
- Analyzed oculomotor nerve axon development, growth cone morphology, and axonal trajectory in mutant mice.
- Investigated Kif21a protein interactions and the effect of mutations on its autoinhibition.
- Examined Map1b knockout mice for CFEOM-like phenotypes.
Main Results:
- Kif21a knockin mice recapitulated CFEOM phenotypes, with superior division axons stalling and inferior division axons branching abnormally.
- Human KIF21A mutations were shown to cause a gain-of-function by attenuating Kif21a autoinhibition, providing in vivo evidence for kinesin autoregulation.
- Map1b was identified as a Kif21a-interacting protein, and Map1b knockout mice also exhibited CFEOM.
Conclusions:
- The study establishes a gain-of-function mechanism for KIF21A mutations in CFEOM1.
- The interaction between KIF21A and Map1b is crucial for normal oculomotor nerve development and implicated in CFEOM1 pathogenesis.
- Perturbations in the axon cytoskeleton, specifically involving KIF21A and Map1b, lead to selective vulnerability in the developing oculomotor nerve.
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