UNC-16 alters DLK-1 localization and negatively regulates actin and microtubule dynamics in Caenorhabditis elegans regenerating neurons

Abstract

Neuronal regeneration after injury depends on the intrinsic growth potential of neurons. Our study shows that UNC-16, a C. elegans JIP3 homologue, inhibits axonal regeneration by regulating initiation and rate of regrowth. This occurs through the inhibition of the regeneration-promoting activity of the long isoform of DLK-1 and independently of the inhibitory short isoform of DLK-1. We show that UNC-16 promotes DLK-1 punctate localization in a concentration-dependent manner limiting the availability of the long isoform of DLK-1 at the cut site, minutes after injury. UNC-16 negatively regulates actin dynamics through DLK-1 and microtubule dynamics partially via DLK-1. We show that post-injury cytoskeletal dynamics in unc-16 mutants are also partially dependent on CEBP-1. The faster regeneration seen in unc-16 mutants does not lead to functional recovery. Our data suggest that the inhibitory control by UNC-16 and the short isoform of DLK-1 balances the intrinsic growth-promoting function of the long isoform of DLK-1 in vivo. We propose a model where UNC-16’s inhibitory role in regeneration occurs through both a tight temporal and spatial control of DLK-1 and cytoskeletal dynamics.

JIP3 links lysosome transport to regulation of multiple components of the axonal cytoskeleton

“…Loss of JIP3 could also have signaling consequences that could propagate beyond its direct subcellular site of action. In addition to interactions with motors, JIP3 (and JIP4) also intersect with signaling in the JNK pathway by acting as a scaffold that regulates the subcellular position and activity of DLK and JNK 25 , 58 – 60 . Additionally, transport defects could impede the ability of lysosomes to act as sites for nutrient and growth factor-dependent activation of the mTORC1 signaling pathway 61 , 62 .…”