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

Abstract

Neuronal connectivity relies on molecular motor-based axonal transport of diverse cargoes. Yet the precise players and regulatory mechanisms orchestrating such trafficking events remain largely unknown. We here report the ATPase Fignl1 as a novel regulator of bidirectional transport during axon navigation. Using a yeast two-hybrid screen and coimmunoprecipitation assays, we showed that Fignl1 binds the kinesin Kif1bβ and the dynein/dynactin adaptor Bicaudal D-1 (Bicd1) in a molecular complex including the dynactin subunit dynactin 1. Fignl1 colocalized with Kif1bβ and showed bidirectional mobility in zebrafish axons. Notably, Kif1bβ and Fignl1 loss of function similarly altered zebrafish motor axon pathfinding and increased dynein-based transport velocity of Rab3 vesicles in these navigating axons, pinpointing Fignl1/Kif1bβ as a dynein speed limiter complex. Accordingly, disrupting dynein/dynactin activity or Bicd1/Fignl1 interaction induced motor axon pathfinding defects characteristic of Fignl1 gain or loss of function, respectively. Finally, pharmacological inhibition of dynein activity partially rescued the axon pathfinding defects of Fignl1-depleted larvae. Together, our results identify Fignl1 as a key dynein regulator required for motor circuit wiring.

IGF 1R regulates retrograde axonal transport of signalling endosomes in motor neurons

“…We discovered that IGF1R inhibition significantly influenced the cellular levels of BICD1, suggesting that changes in BICD1 levels may be the mechanism that underlies the changes in velocity we observed. This is in line with a recent study highlighting the importance of BICD1 in regulating axonal cargo transport . The change in BICD1 levels was driven by newly synthesized axonal BICD1 and occurred within a compatible time frame.…”

Development of motor neurons and motor activity in zebrafish requires F-actin nucleation by Fmn2b

“…The hemisegments with defasciculated axons were classified as stalled RoP axons. Similar defects in RoP-like secondary motor neurons have been reported to occur due to depletion of Kif1b and Fidgetin like-1 in zebrafish (Fassier et al, 2018;Atkins et al, 2019). However, 46.95% of hemisegments had no RoP innervation altogether and were classified as RoP absent.…”

“…In 60 hpf fmn2b mutants, the side branches of RoP motor neurons innervating the horizontal myoseptum were either not detected (46% embryos) or appeared to be stalled at the choice point (44% embryos), i.e., the horizontal myoseptum (Figure 5). RoP-like secondary motor neurons, which follow the same trajectory as RoP primary motor neurons have previously been shown to have pathfinding and stalling defects at the horizontal myoseptum in Fidgetin like-1 and Kif1b mutants (Fassier et al, 2018;Atkins et al, 2019). Similarly, the stalled RoP axons appear defasciculated in 60 hpf fmn2b mutants One of the factors contributing to RoP outgrowth defects leading to the absence of RoP innervation in fmn2b mutants could be the lack of RoP soma as seen in hpf mutant embryos.…”

Microtubule remodelling as a driving force of axon guidance and pruning

“…zebrafish and Xenopus models) have allowed several groups to overcome the above-mentioned limitations. This has contributed to provide novel pieces of information regarding the regulation of MT functions in axon guidance and targeting [22,[24][25][26][72][73][74].…”