Repressed mTORC1 signaling and transient dendritic pruning support axonal regeneration

Abstract

Dendrite degeneration is an early pathological feature following axonal damage, yet its role during successful axonal regeneration remains poorly understood. Using sparse labeling of retinal ganglion cells in adult zebrafish, we show that axonal regeneration is accompanied by a transient phase of dendritic pruning following optic nerve crush. Dendritic pruning occurs during axon elongation and is reversed after brain reinnervation. Although insulin-mTOR signaling is rapidly upregulated immediately after injury, it is subsequently suppressed, coinciding with dendritic pruning and sustained axonal growth. Prolonging mTOR activation through insulin treatment or direct pathway stimulation reduces dendritic pruning in an mTORC1-dependent manner but severely delays axonal regrowth. Together, these findings identify dendritic remodeling as a key temporally regulated component of successful axonal regeneration and reveal a functional trade-off between dendritic preservation and axon regrowth. This balance may represent a critical constraint for promoting CNS repair in mammals.