Restraint of presynaptic protein levels by Wnd/DLK signaling mediates synaptic defects associated with the kinesin-3 motor Unc-104

Abstract

The kinesin-3 family member Unc-104/KIF1A is required for axonal transport of many presynaptic components to synapses, and mutation of this gene results in synaptic dysfunction in mice, flies and worms. Our studies at the Drosophila neuromuscular junction indicate that many synaptic defects in unc-104-null mutants are mediated independently of Unc-104’s transport function, via the Wallenda (Wnd)/DLK MAP kinase axonal damage signaling pathway. Wnd signaling becomes activated when Unc-104’s function is disrupted, and leads to impairment of synaptic structure and function by restraining the expression level of active zone (AZ) and synaptic vesicle (SV) components. This action concomitantly suppresses the buildup of synaptic proteins in neuronal cell bodies, hence may play an adaptive role to stresses that impair axonal transport. Wnd signaling also becomes activated when pre-synaptic proteins are over-expressed, suggesting the existence of a feedback circuit to match synaptic protein levels to the transport capacity of the axon.

An axonal stress response pathway: degenerative and regenerative signaling by DLK

“…More dramatic defects in developmental wiring of the nervous system have been linked to lost regulation of DLK: DLK protein is held in check by a highly conserved ubiquitin ligase, Pam/Highwire/Rpm-1 (PHR) [17–20]. This restraint appears to be important for some axon guidance decisions [17,21], axon termination at correct locations [22,23], assembly of presynaptic machinery [19,20,24••], and elaboration of dendrite branches [25]. Hence restraint verses activity of DLK appears to be important at specific time points in nervous system development.…”

“…Many of the developmental defects associated with unrestrained DLK regulation may actually mimic responses made by neurons to axonal injury. For instance, recent studies using the Drosophila larval neuromuscular junction (NMJ) suggest that activation of DLK signaling promotes synaptic decline [24••,27•], which also occurs at disconnected synapses following injury [28]. Another well known response to axonal injury is a reduction in the injured neuron’s dendritic tree and in the synaptic inputs received by the injured neuron [29,30].…”

“…Also, Li et al . found that DLK signaling restrains the expression levels of presynaptic proteins to match the timing of synaptic maturation and growth [24••]. Premature expression of these abundant structural components of the synapse fully ready to transport and implement these molecules may also result in cellular stress.…”

“…There is a striking correlation between conditions that impair axonal transport and conditions that activate DLK signaling: DLK signaling becomes activated in invertebrate and vertebrate PNS neurons that are treated with cytoskeletal destabilizing agents [47,48•,49,50], or with genetic mutations in the cytoskeletal components spectroplakin, TCP1, Tau, or spectrin [6,47,51•]. Activation also occurs in mutations that impair the kinesin Unc-104 (homologous to Kif1A), which is a major carrier of synaptic vesicle precursors in axons [24••]. Mutations that inhibit DLK signaling rescue the synaptic defects associated with mutations in the kinesin unc-104 [24••].…”

“…Activation also occurs in mutations that impair the kinesin Unc-104 (homologous to Kif1A), which is a major carrier of synaptic vesicle precursors in axons [24••]. Mutations that inhibit DLK signaling rescue the synaptic defects associated with mutations in the kinesin unc-104 [24••]. Other genetic interaction studies in invertebrate peripheral neurons suggest that DLK mediates changes in neuronal morphology caused by mutations that impair cytoskeletal structure [47,52–55].…”