Kinesin-1-mediated axonal transport of CB1 receptors is required for cannabinoid-dependent axonal growth and guidance

Abstract

Endocannabinoids modulate growth cone dynamics and axonal pathfinding through the stimulation of cannabinoid type-1 receptors (CB1R) which function depends on its delivery and precise presentation at the growth cone surface. However, the mechanism involved in the axonal transport of CB1R and its role in eCB signaling remains elusive. Kinesin-1 mutations have been identified in patients with abnormal cortical development and impaired white matter integrity. We found defects in axonal pathfinding and fasciculation in mice lacking the kinesin light chain 1 (KLC1−/−) subunit of the kinesin-1 molecular motor. Reduced levels of CB1R were observed in corticofugal projections and growth cones in KLC1−/−. By live-cell imaging of CB1R-eGFP we characterized the axonal transport of CB1R vesicles in control conditions and the defects in transport that arise in KLC1 deleted neurons. Cofilin activation, which is necessary for actin dynamics during growth cone remodeling, is impaired in KLC1−/− cortex. KLC1−/− neurons showed expanded growth cones that resulted unresponsive to CB1R-induced axonal elongation. Together, our data reveal the relevance of kinesin-1 in CB1R axonal transport and in endocannabinoid signaling during brain wiring.

With the Permission of Microtubules: An Updated Overview on Microtubule Function During Axon Pathfinding

“…The recent analysis of a mutant mice lacking the kinesin-1 light chain KLC1 has revealed hypoplasia of the internal capsule tract, that includes corticofugal and thalamocortical axons. The innervation defects were found to be caused by an impaired kinesin-1-dependent axonal transport of the cannabinoid type-1 receptors (CB1R), and the subsequent axon unresponsiveness to endocannabinoids signaling ( Saez et al, 2020 ).…”

New Insights Into Functions of IQ67-Domain Proteins

“…Kinesin light chain is generally located at the end of kinesin and participates in cargo transport ( Saez et al, 2020 ). Therefore, IQD may co-localize with microtubules in addition to its classic nuclear localization, a finding subsequently confirmed using high-resolution fluorescence microscopy.…”

Trans-Axonal Signaling in Neural Circuit Wiring

“…Along with classical guidance cues, other signaling molecules regulate axon fasciculation in addition to their other better-known functions. Endocannabinoids, for instance, have been identified as guidance cues regulating axon pathfinding and elongation in mouse and xenopus [ 74 ], and deletion of the cannabinoid receptor CB 1 R from mouse cortical neurons in vivo causes a defasciculation of their axons [ 75 , 76 ]. A recent study reported that Kinesin-1 regulates the trafficking and sub-cellular localization of CB 1 R in mouse cortical neurons, thereby modulating endocannabinoid signaling and axon fasciculation [ 76 ].…”