Fueling axonal regeneration: dendritic energy to the rescue?

Abstract

AbstractUp to now neuroregenerative research mainly focused on improving axonal regrowth, leaving the dendrites, which form an essential component of the neuronal circuit, largely unstudied. Nevertheless, subtle changes in the dendritic arbors of neurons are one of the first stages of various neurodegenerative diseases, leading to dysfunctional neuronal networks and ultimately cellular death. Maintaining dendrites is therefore considered an essential neuroprotective strategy. Here, we postulate the intriguing hypothesis, that dendritic shrinkage is an important stimulant to boost axonal regeneration, and thus that preserving dendrites might not be the ideal therapeutic method to regain a full functional network upon CNS damage. Indeed, our study in zebrafish, a versatile animal model with robust regenerative capacity, recently unraveled that dendritic retraction is evoked prior to axonal regrowth after optic nerve crush (ONC) injury, and that the retinal ganglion cell (RGC) dendrites regenerate after axonal repair. This orderly sequence of neurite outgrowth is a recapitulation of development, where axogenesis also precedes dendritogenesis. Strikingly, inhibiting RGC dendritic pruning upon damage perturbed axonal regeneration in zebrafish. This constraining effect of dendrites on axonal regrowth has sporadically been proposed in literature. In line with this, we observed an increased loss of RGC dendrites and reduced dendritic arbor complexity in the mouse retina when axonal regeneration was induced by inflammatory stimulation. All together, these data point towards a conserved neuronal remodeling mechanism, where dendritic pruning upon neuronal injury supports axonal regeneration. We now hypothesize that a reprogramming and relocation of the neuronal energy production machinery towards the axon is needed for regeneration, a process in which the shrinking dendrites might play a key role. To test this idea, a combination of state‐of‐the‐art in vitro and in vivo research approaches are being pursued. We are characterizing, in the axonal versus dendritic cell compartment, the subcellular and molecular players modulating energy production and enabling axonal regrowth of injured CNS neurons. Overall, our findings could generate pivotal insights into how re‐directing intra‐neuronal energy channelling may promote neuronal repair in the mammalian CNS.