The limited ability for axonal repair after spinal cord injury underlies long-term functional impairment. DLK (MAP3K12) is an evolutionarily conserved MAP3K implicated in neuronal injury signaling from C. elegans to mammals. However, whether DLK or its close homologue LZK (MAP3K13) regulates axonal repair in the mammalian spinal cord remains unknown. Here we assess the role of endogenous DLK and LZK in the regeneration and compensatory sprouting of corticospinal tract (CST) axons in mice of both sexes with genetic analyses in a regeneration competent background provided by PTEN deletion. We found that inducible neuronal deletion of both DLK and LZK, but not either kinase alone, abolishes PTEN deletion-induced regeneration and sprouting of CST axons, and reduces naturally-occurring axon sprouting after injury. Thus, DLK/LZK-mediated injury signaling operates not only in injured neurons to regulate regeneration, but also unexpectedly in uninjured neurons to regulate sprouting. Deleting DLK and LZK does not i...