Astrocyte-specific FoxF2 modulates immune and myelin repair: Evidence from multiple sclerosis lesions and an animal model

As multiple sclerosis (MS) progresses, myelin repair becomes inefficient. To gain insight into the underlying causes, we RNA-sequenced postmortem brain tissues from 4 and 6 patients, comparing remyelinating versus chronically active MS lesions. We identified the transcription factor FoxF2 as highly expressed within remyelinating lesions. Immunohistochemistry and in situ hybridization showed FoxF2 co-expression in GFAP-positive astrocytes, suggesting a subpopulation of astrocytes with a potential role in repair. To investigate how FoxF2 may influence repair, we examined cuprizone (CPZ)-induced de- and remyelination in CreERT2 FoxF2 flox/flox conditional knockout (FoxF2 KO) mice. In the absence of FoxF2, RNA sequencing of the isolated corpus callosum (CC) showed high gene activation during demyelination and reduced gene activation during remyelination. Upregulated genes in FoxF2 KO mice were related to immune functions and metabolism. Specifically, upregulation of MHC-II and TNF-associated pathway genes, while astrocyte-specific FoxF2 deletion significantly reduced Tgfb2 and Tgfbr2 expression, implicating disrupted TGF-β signaling. The FoxF2 KO mice exhibited upregulation of ribosomal and sphingolipid metabolism genes during demyelination, while structurally related genes, including Mog expression, were impaired in the FoxF2 KO mice. Using network analysis to group highly correlated genes in the CC transcriptome, we identified gene regulatory network (GRN) changes. GRN analysis revealed the loss of FoxF2-associated modules (e.g., Foxf2–Bach2, Nfe2l1–Mafg), indicating impaired coordination of anti-inflammatory and regenerative pathways. In conclusion, analysis of MS white matter (WM) lesions and subsequent experimental data demonstrates that FoxF2 plays a role in regulating repair and gene networks associated with immune regulation, metabolism, and structural remodeling. • Identification of the transcription factor FoxF2 in remyelinating brain lesions from patients with progressive multiple sclerosis. • FoxF2 influences myelin synthesis, immune regulation, metabolism, and structural remodeling in mice. • Astrocytes are the key expressors of FoxF2 and can be linked to the co-expression of TGFβR2 and its ligand TGFβ2 during remyelination. • Further studies on the temporal dynamics of FoxF2 and its associated gene networks may provide additional insights into CNS repair processes.