Sengupta Ghosh et al. describe how the kinase DLK activates a specific pool of JNK molecules to promote neuronal degeneration during development.

Developing sensory neurons compete for nerve growth factor (NGF); the losing cells die or retract their axons, thereby refining the innervation of peripheral targets. Sengupta Ghosh et al. generated mice lacking the mixed lineage kinase DLK and found that cell death was reduced in the peripherally projecting neurons of these animals. Dorsal root ganglion neurons isolated from DLK-null mice grew normally but were protected from axon degeneration and apoptosis after NGF withdrawal.

The researchers looked for signaling pathways altered in DLK-null neurons and found that, in the absence of DLK, NGF withdrawal failed to stimulate JNK, a MAP kinase that promotes neuronal degeneration. Yet basal levels of JNK activity—essential for normal neuronal function—remained unchanged in DLK-null neurons, indicating that DLK activates a subset of JNK molecules after NGF removal.

DLK bound to JIP3, a scaffold protein that also interacts with JNK. Neurons lacking JIP3 were also protected from JNK activation and neuron degeneration in the absence of NGF, suggesting that DLK and JIP3 form a specific signaling complex that activates JNK to promote axon degeneration and cell death without affecting other JNK functions. JNK promoted neuronal death by phosphorylating c-Jun, but this transcription factor wasn't required for axon degeneration. Senior author Joseph Lewcock now wants to investigate how NGF withdrawal stimulates DLK's activity.

Sengupta Ghosh
et al
J. Cell Biol.