A Gata4-Loxl2 axis controls ECM remodeling to enable scar-free spinal cord regeneration in zebrafish.

Spinal cord injury in mammals triggers fibrotic scar formation that impedes axon regrowth, whereas zebrafish regenerate and recover motor function without persistent fibrosis. Here, we identify the transcription factor Gata4 as a regulator of regeneration-associated extracellular matrix (ECM) remodeling. Following injury, gata4 is induced predominantly in ependymo-radial glial cells (ERGs). Gata4 preserves ERG identity and suppresses a fibroblast-like transcriptional program enriched for ECM genes. Loss of Gata4 increases expression of the collagen cross-linking enzyme Loxl2b, resulting in excessive collagen cross-linking, matrix stiffening, and a regeneration-inhibitory ECM environment. These changes delay glial and axonal bridging and impair motor recovery. Pharmacological inhibition of Loxl2b rescues ECM organization, tissue bridging, and functional recovery. Injury-induced gata4 expression depends in part on Hif-1α signaling and activation of an injury-responsive cis-regulatory element. Together, these findings identify a Gata4-Loxl2b axis linking glial cell state to ECM mechanics during spinal cord regeneration.