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

Abstract

Spinal cord injury in mammals causes permanent loss of sensory and motor function due to scar formation obstructing axon regrowth. In contrast, zebrafish fully regenerate their spinal cord without lasting fibrosis. Here, we identify the transcription factor Gata4 as a key positive regulator of regeneration. After injury, gata4 expression is predominantly upregulated in ependymo-radial glial cells and in glial cells extending processes toward sites of tissue bridging. Gata4 preserves glial identity and orchestrates regenerative extracellular matrix (ECM) remodeling. Gata4 loss biases glial cells toward a fibroblast-like state with upregulated Loxl2b, a collagen cross-linking enzyme, and can also increase Loxl2b in nearby non-glial cells. Excess Loxl2b activity promotes pathological crosslinking and formation of a rigid, fibrotic matrix impairing glial and axonal bridging across the lesion, greatly reducing motor recovery. Pharmacological inhibition of Loxl2b in gata4 mutants substantially rescues ECM organization, tissue bridging, and functional recovery. Injury-induced gata4 expression depends, at least in part, on Hif1 signaling and activation of a short injury-responsive enhancer. We identify the Gata4-Loxl2b axis as a central regulator of and potential therapeutic target for scar-free spinal cord repair.