Deletion of wfs1 Impairs Oligodendrocyte Precursor Cells Dorsal Distribution and Myelination Through the wfs1-hmgcs1 Axis in Zebrafish

Wolfram syndrome (WS) is a neurodegenerative disorder caused by mutations in the endoplasmic reticulum (ER) transmembrane protein WFS1. Mutations in WFS1 lead to ER stress and dysregulated calcium signaling, resulting in progressive neurological dysfunction. Myelination is a core pathological process in various central nervous system (CNS) diseases. However, the role of WFS1 in oligodendrocyte development and myelination remains unknown. Here, using CRISPR-Cas9-generated wfs1a/wfs1b double-knockout (wfs1−/−) zebrafish, we demonstrated that wfs1 deficiency significantly delayed the dorsal distribution of oligodendrocyte precursor cells (OPCs) along Mauthner axons. Furthermore, wfs1 mutation was associated with early hypomyelination of axons at 5 dpf, with partial recovery observed by 8 dpf. Mechanistically, combined transcriptomic and pharmacological analysis revealed that wfs1 mutation led to the suppression of the steroid biosynthesis pathway through downregulation of hmgcs1, which encodes the upstream condensation enzyme of the mevalonate pathway and supplies substrate for the downstream rate-limiting enzyme HMGCR, thereby potentially reducing isoprenoid precursor availability. Pharmacological supplementation with geranylgeraniol (GGOH) specifically rescued dorsal distribution defects, supporting involvement of the isoprenylation pathway, although direct regulation of hmgcs1 by wfs1 and complete rescue of myelin structure require further mechanistic validation. Taken together, our study supports a novel wfs1-hmgcs1 axis, which may regulate dorsal distribution and myelination through the isoprenylation pathway; notably, classical ER stress markers were also concurrently upregulated in wfs1−/− larvae, although whether the isoprenylation deficiency and ER stress act independently or synergistically remains to be determined. These findings provide new insights into WS-associated early hypomyelination and suggest hmgcs1 as a potential therapeutic target for myelin defects caused by WS.