To grow or not to grow: inhibitory control of functional axon regeneration by UNC-16/JIP3

12-04-2019

Sem Koushika 12Abr19 Ls 001

Neurons in the adult nervous system have a limited ability to regenerate after injury. The extent of neuronal regeneration after injury depends on the intrinsic growth potential of neurons and their extracellular environment, both influenced by several genes. We show that UNC-16/JIP3, a C. elegans JIP3 homologue that scaffolds MAP kinases, plays an inhibitory role that controls time of regrowth initiation and rate of axonal regrowth after axotomy in C. elegans touch neurons. Elevated UNC-16/JIP3 leads to no change in the time of regrowth initiation but a lower rate of regrowth. UNC-16’s inhibitory role is dependent on Dual Leucine Zipper Kinase-1 (DLK-1), an essential MAPKKK for neuronal regeneration. DLK-1 has two isomers, long and short, of these, DLK-1 long promotes regeneration while DLK-1 short inhibits regeneration. UNC-16/JIP3 inhibits the regeneration promoting activity of DLK-1 long but acts additively to and independently of DLK-1 short. UNC-16/JIP3 promotes DLK-1 punctate localization in a concentration dependent manner limiting DLK-1 long availability at the cut site minutes after injury. UNC-16 negatively regulates actin dynamics dependent on DLK-1 and microtubule dynamics independent of DLK-1. Both these cytoskeletal processes together alter both the initiation (through a growth cone with more protrusive activity) and the rate of regrowth. The faster regeneration seen in unc-16 does not lead to functional recovery but slower regeneration seen when UNC-16 is over-expressed shows functional recovery comparable to wild type animals. We propose a model where UNC-16/ JIP3 plays its inhibitory role through tight temporal and spatial control of DLK-1 function. The dual inhibitory control by both UNC-16 and DLK-1 short calibrate the intrinsic growth promoting function of DLK-1 long in vivo. Further that a slower regeneration rate may assist in functional recovery of the injured neuron.

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