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

SAEZ, TRINIDAD M. M.; FERNANDEZ BESSONE, IVÁN; RODRIGUEZ, MARÍA S.; ALLOATTI, MATÍAS; OTERO, MARÍA G.; CROMBERG, LUCAS E.; POZO DEVOTO, VICTORIO M.; OUBIÑA, GONZALO; SOSA, LUCAS; BUFFONE, MARIANO G.; GELMAN, DIEGO M.; FALZONE, TOMÁS L.

DEVELOPMENT

COMPANY OF BIOLOGISTS LTD

Año: 2020 vol. 147

0950-1991

Endocannabinoids (eCB) modulate growth cone dynamics and axonalpathfinding through the stimulation of cannabinoid type-1 receptors(CB1R), the function of which depends on their delivery and precisepresentation at the growth cone surface. However, the mechanisminvolved in the axonal transport of CB1R and its transport role in eCBsignalingremains elusive.Asmutations inthekinesin-1molecularmotorhave been identified in patients with abnormal cortical development andimpaired white matter integrity, we studied the defects in axonalpathfinding and fasciculation in mice lacking the kinesin light chain 1(Klc1−/−) subunit of kinesin-1. Reduced levels of CB1R were found incorticofugal projections and axonal growth cones in Klc1−/− mice. Bylive-cell imaging of CB1R-eGFP we characterized the axonal transportof CB1R vesicles and described the defects in transport that arise afterKLC1 deletion. Cofilin activation, which is necessary for actin dynamicsduring growth cone remodeling, is impaired in the Klc1−/− cerebralcortex. In addition, Klc1−/− neurons showed expanded growth conesthat were unresponsive to CB1R-induced axonal elongation. Together,our data reveal the relevance of kinesin-1 inCB1R axonal transport andin eCB signaling during brain wiring.