Kinesin-1 sorting in axons controls the differential retraction of arbor terminals

Abstract

The ability of neurons to generate multiple arbor terminals from a single axon is crucial for establishing proper neuronal wiring. Although growth and retraction of arbor terminals are differentially regulated within the axon, the mechanisms by which neurons locally control their structure remain largely unknown. In the present study, we found that the kinesin-1 (Kif5 proteins) head domain (K5H) preferentially marks a subset of arbor terminals. Time-lapse imaging clarified that these arbor terminals were more stable than others, because of a low retraction rate. Local inhibition of kinesin-1 in the arbor terminal by chromophore-assisted light inactivation (CALI) enhanced the retraction rate. The microtubule turnover was locally regulated depending on the length from the branching point to the terminal end, but did not directly correlate with the presence of K5H. By contrast, F-actin signal values in arbor terminals correlated spatiotemporally with K5H, and inhibition of actin turnover prevented retraction. Results from the present study reveal a new system mediated by kinesin-1 sorting in axons that differentially controls stability of arbor terminals.

It takes a village to raise a branch: Cellular mechanisms of the initiation of axon collateral branches

“…Thus, KIF2A plays an important role in suppression of collateral branch extension, but a role in branch initiation was not observed. Similarly, a recent study found that Kinesin-1 (KIF5) accumulates at the tips of neurites within the axon arbor of cerebellar granule neurons and suppresses their retraction, resulting in stabilization and subsequent increased growth (Seno et al, 2016). Moreover, a role for microtubule motors in the formation of collateral branches along sensory axons in response to treatment with NGF is suggested by a study using ciliobrevin D, an inhibitor of the retrograde motor protein dynein (Sainath and Gallo, 2015).…”

Mechanisms of Differential Branch Growth Control in the Single Axonal Arbor

“…Axonal processes with the motor domain of kinesin enriched at the terminals exhibit lower retraction rates. Furthermore, local inhibition of kinesin function by chromophore-assisted light inactivation increases the retraction rate of the target process but not that of the neighboring process [11]. These results suggest that a process-dependent difference in microtubule stability within a single arbor contributes to differential terminal retraction by regulating kinesin-mediated axonal transport.…”

“…Among the various posttranslational modifications of tubulins, tyrosination and acetylation are affected by microtubule stability, that is, stable microtubules contain more detyrosinated and acetylated tubulins [27]. In axonal arbors, microtubules near growth cones are unstable and abundant with tyrosinated and deacetylated tubulins, whereas microtubules in longer processes are more stable than those in shorter processes at the region near the branch point [11,28,29]. Consistent with these observations, longer processes are more enriched with detyrosinated and acetylated microtubules than their neighboring shorter processes when compared at the same distance from the axonal branch point (Fig.…”

“…As an axon extends, it becomes thinner, and the primary axonal process and its branches become less distinct from one another. Furthermore, the main axon can disappear by retracting, or the branches can behave as the "main axon," or both [10,11]. Thus, the preexisting axonal process does not persist as a morphologically and functionally distinct process.…”

Differential retraction of axonal arbor terminals mediated by microtubule and kinesin motor

“…During neuronal polarization, microtubule turnover becomes slower in longer axonal processes compared with minor processes 15 . When the microtubule turnover of arbor branch pairs is compared in the area proximal to the branching point, it is more stable in the longer process than in the shorter one 16 . Consequently, the ratio of dTyr and Ac of tubulin is higher in longer arbor processes.…”