Kif1B Interacts with KBP to Promote Axon Elongation by Localizing a Microtubule Regulator to Growth Cones

Abstract

Delivery of proteins and organelles to the growth cone during axon extension relies on anterograde transport by kinesin motors. Though critical for neural circuit development, the mechanisms of cargo-specific anterograde transport during axon extension are only starting to be explored. Cargos of particular importance for axon outgrowth are microtubule modifiers, such as SCG10 (Stathmin-2). SCG10 is expressed solely during axon extension, localized to growth cones, and essential for axon outgrowth; however, the mechanisms of SCG10 transport and activity were still debated. Using zebrafish mutants and in vivo imaging, we identified the Kif1B motor and its interactor Kif1 binding protein (KBP) as critical for SCG10 transport to axon growth cones and complete axon extension. Axon truncation in kbp st23 mutants can be suppressed by SCG10 overexpression, confirming the direct relationship between decreased SCG10 levels and failed axon outgrowth. Live imaging revealed that the reduced levels of SCG10 in kbp st23 mutant growth cones led to altered microtubule stability, defining the mechanistic basis of axon truncation. Thus, our data reveal a novel role for the Kif1B-KBP complex in the anterograde transport of SCG10, which is necessary for proper microtubule dynamics and subsequent axon extension.

Kif1bp loss in mice leads to defects in the peripheral and central nervous system and perinatal death

“…Kinesins (KIF proteins) are a large family of microtubule-based intracellular motors that transport cargo from one part of the cell to another. Cell biological approaches revealed that KIF1BP interacts with a subset of kinesins including KIF1A, KIF1B, KIF1C, KIF3A, KIF13B, KIF14, KIF15 and KIF18A 9 – 11 . Studies using cell lines and zebrafish mutants suggest the main role of KIF1BP is to regulate axon extension.…”

FIGNL1 associates with KIF1Bβ and BICD1 to restrict dynein transport velocity during axon navigation

“…4 D; Fassier et al, 2018). These data suggest that Fignl1 may not be a Kif1bβ cargo, unlike SCG10 (Drerup et al, 2016).…”

Intracellular cargo transport by kinesin-3 motors

“…Interestingly, the presence of BICD2 increases the force generation and processivity of dynein/dynactin [127,128], demonstrating that these cargo adapter proteins regulate motor activity and could act as switches to control transport directionality within a complex containing two opposing motors. Other control mechanisms could come from accessory proteins such as kinesin binding protein (KBP), which has been shown to stimulate KIF1B, but inhibit KIF1A mediated bidirec tional transport [28,129]. If the activity of such regulato ry proteins were spatially controlled, this would enable directional switching of transport complexes in the pres ence of opposing motors.…”