Golgi-mediated microtubule nucleation is associated with initiation of vertebrate peripheral neuron regeneration

Peripheral neurons have the potential to regenerate following injury, yet a poor understanding of the cell intrinsic drivers of this process have prevented clinical exploitation. Using in vitro and in vivo models, we define a conserved mechanistic basis for initiation of adult human and rat peripheral neuron regeneration that highlights the Golgi as a major driver of peripheral neuron regeneration. Acute injury first induces somatic Golgi fragmentation followed by rapid re-compaction as a pre-requisite to regeneration. Initiation of axon regeneration is then triggered through transient stepwise recruitment of the microtubule nucleation factors AKAP9 and γ-tubulin, resulting in Golgi-mediated microtubule nucleation. Consequently, disruption of Golgi compaction or AKAP9 and γ-tubulin recruitment compromises induction of microtubule nucleation and initiation of regeneration. This work redefines our understanding of the conserved cell-intrinsic mechanisms initiating peripheral neuron regeneration and identifies Golgi-mediated microtubule nucleation as a key therapeutic target in an area of clinical unmet need.