Loss of CRMP4 in astrocytes causes reduced scar formation and functional recovery of motor function after spinal cord injury.

Reactive astrocytes play a central role in shaping the post-injury microenvironment after spinal cord injury (SCI), yet the molecular mechanisms governing their proliferative expansion and contribution to scar architecture remain incompletely defined. Conditional deletion of CRMP4 in astrocytes significantly reduced astrocyte proliferation, altered scar organization, and attenuated the inflammatory milieu surrounding the lesion, including reduced microglial activation. These changes were accompanied by significantly improved locomotor recovery, as assessed by the Basso Mouse Scale (BMS) locomotor rating scale, indicating enhanced functional restoration after SCI. Our findings suggest that CRMP4 promotes the expansion of reactive astrocyte subsets that shape the inhibitory niche surrounding the lesion core, thereby restricting axonal regeneration and limiting functional recovery after SCI. Single-cell RNA sequencing (scRNA-seq) analysis of a public dataset revealed that Crmp4 expression is enriched in proliferative, progenitor-like astrocyte subpopulations that contribute to scar formation, including subclusters corresponding to the G2/M phases of the cell cycle. Together, this study identifies astrocytic CRMP4 as a key molecular determinant of reactive astrocyte dynamics and scar architecture after SCI, providing new insight into cell-type-specific regulation of glial responses in central nervous system injury.