Human CFEOM1 Mutations Attenuate KIF21A Autoinhibition and Cause Oculomotor Axon Stalling

Abstract

SUMMARY The ocular motility disorder “Congenital fibrosis of the extraocular muscles type 1″ (CFEOM1) results from heterozygous mutations altering the motor and 3rd coiled-coil stalk of the anterograde kinesin, KIF21A. We demonstrate that Kif21a knock-in 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.

Mutant α2-chimaerin signals via bidirectional ephrin pathways in Duane retraction syndrome

“…However, upon addition of PMA to broadly activate α2-chimaerin irrespective of upstream pathway activation, mutant cultures had a marked reduction in Rac-GTP levels compared with WT cultures, demonstrating that the endogenous L20F amino acid substitution enhances GAP activity of α2-chimaerin upon activation (Supplemental Figure 1F), similar to previous overexpression experiments in non-neuronal cells (3, 9). innervated by one or two aberrant oculomotor nerve branches arising at established oculomotor growth cone decision regions (27): the proximal branch formed from the superior oculomotor nerve division branch-point off the main oculomotor trunk, while the distal branch arose from the inferior oculomotor nerve division branch-point to the medial rectus, inferior rectus, and inferior oblique muscles ( Figure 2B). Thus, the oculomotor nerve provides compensatory misinnervation to the lateral rectus in the absence of the abducens nerve, confirming human autopsy and electromyographic data.…”

“…Images were processed in 3D using Imaris (Bitplane) to identify similar z-planes between embryos. See Supplemental Methods for measurement parameters (27).…”

Microtubule Organization and Microtubule-Associated Proteins (MAPs)

“…Recent studies suggest that MAP1B preferably associates to dynamic, tyrosinated MTs Tymanskyj et al 2012;Utreras et al 2008). MAP1B also interacts with other MT-interacting proteins, including tubulin-tyrosine ligase and EB1/EB3, dynein regulators like LIS1, scaffolding proteins such as dystonin-α2, and motor protein KIF21A (Cheng et al 2014;Villarroel-Campos and Gonzalez-Billault 2014). The role of MAP1B in axon formation has been studied for many years (GordonWeeks and Fischer 2000).…”

“…It is widely believed that MAP1B could act as a scaffold for many of the above mentioned factors by anchoring them to the MT cytoskeleton or controlling their activity and localization. MAP1B has been linked to various neurodegenerative disorders, including Parkinson's disease (Chan et al 2014;Jensen et al 2000), Alzheimer's disease (Gevorkian et al 2008;Good et al 2004;Hasegawa et al 1990), giant axonal neuropathy (Allen et al 2005;Ding et al 2002), spinocerebellar ataxia type 1 (Opal et al 2003), fragile X syndrome (Brown et al 2001;Lu et al 2004;Zalfa et al 2003), and the eye-related muscular disorder congenital fibrosis of the extraocular muscles type 1 (CFEOM) (Cheng et al 2014). …”

Kinesin superfamily proteins and the regulation of microtubule dynamics in morphogenesis

“…Recent studies have shown that these atypical KIFs play fundamental roles in cellular morphogenesis. In knockout mice in which these KIFs have been deleted, cellular morphology is strongly affected (Cheng et al 2014;Zhou et al 2009;Niwa et al 2012;Homma et al 2003;He et al 2014). KIF2A and KIF21A have been identified as causes of human neuronal diseases (Poirier et al 2013;Yamada et al 2003).…”