Spinal cord injury (SCI) causes permanent motor deficits primarily due to neuronal apoptosis and inadequate axonal regeneration, with the c-Jun N-terminal kinase (JNK)/c-Jun pathway playing a dual role in neurodegeneration and regeneration. Here, we identified Nyap1 as a spatiotemporally limited modulator that rearranges JNK signaling to shift its function from degeneration to regeneration. Time-resolved transcriptomic profiling showed Nyap1 was dynamically upregulated as a hub gene during the acute-to-subacute phase of SCI. Nyap1 was associated with altered subcellular distribution of p-JNK, with increased cytoplasmic retention, with overexpression enriching p-JNK in the cytosol and limiting nuclear translocation-sufficient to drive regenerative transcription without inducing apoptosis. This interaction was associated with modulation of apoptosis-related and regeneration-related signaling, including changes in the Bcl-2/Bax ratio, caspase-3 activation, c-Jun phosphorylation, and GAP43 expression, with these effects abrogated by JNK inhibition. In vivo, Nyap1 overexpression preserved thoracic spinal motor neurons, promoted descending propriospinal tract (DPST) axonal regeneration, enhanced lumbar motor neuron dendritic arborization and synaptic input, and reduced lesion cavity volume. These structural improvements were accompanied by better gait coordination, neuromuscular reinnervation, and translesional motor conduction. Our findings support a model in which Nyap1 is associated with spatial redistribution of p-JNK-related signaling, linking neuronal survival with circuit-level plasticity after SCI, highlighting its potential as a therapeutic candidate for CNS trauma.
Li et al. (Sat,) studied this question.