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Neuron DOI:10.1016/j.neuron.2014.02.038

Human CFEOM1 mutations attenuate KIF21A autoinhibition and cause oculomotor axon stalling.

Publication TypeJournal Article
Year of Publication2014
AuthorsCheng, L, Desai, J, Miranda, CJ, Duncan, JS, Qiu, W, Nugent, AA, Kolpak, AL, Wu, CC, Drokhlyansky, E, Delisle, MM, Chan, W-M, Wei, Y, Propst, F, Reck-Peterson, SL, Fritzsch, B, Engle, EC
Date Published2014 Apr 16
KeywordsAge Factors, Animals, Animals, Newborn, Axons, Cell Count, Disease Models, Animal, Embryo, Mammalian, Eye Diseases, Hereditary, Eye Movements, Fibrosis, Gene Expression Regulation, Green Fluorescent Proteins, HEK293 Cells, Humans, Kinesin, Mice, Mice, Transgenic, Microtubule-Associated Proteins, Mutation, Neural Pathways, Ocular Motility Disorders, Oculomotor Nerve

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.


Alternate JournalNeuron
PubMed ID24656932
PubMed Central IDPMC4002761
Grant ListR01 EY013583 / EY / NEI NIH HHS / United States
P30 HD018655 / HD / NICHD NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
P30 CA06516 / CA / NCI NIH HHS / United States
P30 HD18655 / HD / NICHD NIH HHS / United States
P30 CA006516 / CA / NCI NIH HHS / United States