Human CFEOM1 Mutations Attenuate KIF21A Autoinhibition and Cause Oculomotor Axon Stalling

被引：86

作者：

Cheng, Long ^{[1
,2
,3
,7
]}

Desai, Jigar ^{[1
,2
,3
,7
]}

Miranda, Carlos J. ^{[3
]}

Duncan, Jeremy S. ^{[13
]}

Qiu, Weihong ^{[9
]}

Nugent, Alicia A. ^{[1
,2
,8
]}

Kolpak, Adrianne L. ^{[1
,2
,7
]}

Wu, Carrie C. ^{[1
,2
]}

Drokhlyansky, Eugene ^{[3
]}

Delisle, Michelle M. ^{[1
,2
,3
]}

Chan, Wai-Man ^{[1
,2
,3
,7
,11
]}

Wei, Yan ^{[1
,2
]}

Propst, Friedrich ^{[12
]}

Reck-Peterson, Samara L. ^{[9
]}

Fritzsch, Bernd ^{[13
]}

Engle, Elizabeth C. ^{[1
,2
,3
,4
,5
,6
,7
,8
,10
,11
,14
]}

机构：

[1] Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA

[2] Boston Childrens Hosp, FM Kirby Neurobiol Ctr, Boston, MA 02115 USA

[3] Boston Childrens Hosp, Program Genom, Boston, MA 02115 USA

[4] Boston Childrens Hosp, Dept Med Genet, Boston, MA 02115 USA

[5] Boston Childrens Hosp, Dept Ophthalmol, Boston, MA 02115 USA

[6] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA

[7] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA

[8] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA

[9] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA

[10] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02115 USA

[11] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

[12] Univ Vienna, Dept Biochem & Cell Biol, Max F Perutz Labs, A-1030 Vienna, Austria

[13] Univ Iowa, Dept Biol, Coll Liberal Arts & Sci, Iowa City, IA 52242 USA

[14] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

来源：

NEURON | 2014年 / 82卷 / 02期

关键词：

EXTRAOCULAR-MUSCLES TYPE-1; CONGENITAL FIBROSIS; PROTEIN; 1B; MICROTUBULE DYNAMICS; NERVOUS-SYSTEM; KINESIN KIF21A; MAP1B; ABNORMALITIES; GUIDANCE; BINDING;

D O I：

10.1016/j.neuron.2014.02.038

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：334 / 349

页数：16

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