Grip and slip of L1-CAM on adhesive substrates direct growth cone haptotaxis

Abstract

SignificanceCell migration directed by substrate-bound chemical cues is called haptotaxis. This study shows that grip and slip between the cell adhesion molecule (CAM) L1-CAM and the adhesive substrates, which occur asymmetrically under the growth cone, direct growth cone migration mediated by laminin. This mechanism is disrupted in a human patient of L1-CAM syndrome, suffering corpus callosum agenesis and corticospinal tract hypoplasia. These findings provide a conceptual framework for understanding the regulation and dysregulation of cell migration on the bases of force generation.

Gradient-reading and mechano-effector machinery for netrin-1-induced axon guidance

“…To assess shootin1a-mediated clutch coupling on laminin, we measured F-actin retrograde flow in growth cones on laminin. Consistent with previously reported data ( Abe et al, 2018 ), the F-actin retrograde flow rate in control growth cones on laminin was 2.3 ± 0.3 μm/min ( Figure 7—figure supplement 4D ). As in the case of growth cones on L1-CAM ( Figure 6A and B ), overexpression of shootin1a (1-125) increased significantly the retrograde flow rate under these conditions ( Figure 7—figure supplement 4D ), indicating that inhibition of the shootin1a–L1-CAM interaction also disrupts F-actin-adhesion coupling in growth cones on laminin.…”

“…Laminins are widely used substrates for axon guidance assays ( Turney and Bridgman, 2005 ; Nichol et al, 2016 ); L1-CAM on growth cones interacts directly with laminin presented on the substrate ( Hall et al, 1997 ; Abe et al, 2018 ). To examine whether the shootin1a–L1-CAM interaction mediates netrin-1–induced axon guidance generally, we performed an axon guidance assay on an alternative substrate, laminin.…”

Forces to Drive Neuronal Migration Steps

“…The tip of an extending axon also bears a growth cone ( Lowery and Van Vactor, 2009 ), and axonal growth cones produce traction forces for axon outgrowth and guidance ( Chan and Odde, 2008 ; Koch et al, 2012 ; Abe et al, 2018 ; Baba et al, 2018 ). Decades of analyses of axonal growth cones have revealed a key machinery to generate traction forces for growth cone migration.…”

“…Shootin1a interacts with F-actin retrograde flow through its association with the F-actin-interacting protein cortactin ( Kubo et al, 2015 ). Shootin1a also interacts with the cell adhesion molecule L1-CAM ( Baba et al, 2018 ), which binds to the ECM protein laminin ( Abe et al, 2018 ) as well as to L1-CAM expressed on neighboring cells ( Lemmon et al, 1989 ), thereby mechanically coupling the F-actin retrograde flow with the adhesive substrates. The shootin1a-mediated actin–adhesion coupling generates traction forces for axon outgrowth ( Kubo et al, 2015 ) and axon guidance induced by diffusible and substrate-bound chemical cues ( Abe et al, 2018 ; Baba et al, 2018 ).…”

“…Shootin1a also interacts with the cell adhesion molecule L1-CAM ( Baba et al, 2018 ), which binds to the ECM protein laminin ( Abe et al, 2018 ) as well as to L1-CAM expressed on neighboring cells ( Lemmon et al, 1989 ), thereby mechanically coupling the F-actin retrograde flow with the adhesive substrates. The shootin1a-mediated actin–adhesion coupling generates traction forces for axon outgrowth ( Kubo et al, 2015 ) and axon guidance induced by diffusible and substrate-bound chemical cues ( Abe et al, 2018 ; Baba et al, 2018 ). N-cadherin–catenin complexes were also reported to mediate actin–adhesion coupling at the axonal growth cone ( Bard et al, 2008 ; Garcia et al, 2015 ).…”