FGF signaling induces disease-associated oligodendrocyte states and drives myelin pathology
Myelin integrity is essential for normal central nervous system (CNS) function and is disrupted in neuroinflammatory and neurodegenerative disorders, including multiple sclerosis and Alzheimer's disease. In these settings, myelin-forming oligodendrocytes adopt a conserved disease-associated transcriptional state, termed disease-associated oligodendrocytes (DAOs). How DAOs arise, the signals that drive their induction, and whether they actively contribute to pathology remain poorly understood. Here we show that FGF signaling instructs mature oligodendrocytes to enter disease-associated states that are sufficient to trigger myelin pathology. By screening disease-linked secreted factors, we identify FGF1 and FGF2 as potent inducers of a DAO-like state in purified oligodendrocyte cultures, characterized by transcriptional reprogramming and myelin-membrane shedding. In vivo, activating oligodendrocyte FGF signaling is sufficient to elicit DAO programs and myelin disruption, whereas inhibiting FGF signaling suppresses DAO induction in a mouse model of multiple sclerosis. Finally, analysis of post-mortem multiple sclerosis tissue reveals a concordant DAO-like state associated with increased engagement of the FGF/FGFR axis. Collectively, these studies define a regulated mechanism of DAO formation linked to myelin disruption and position mature oligodendrocytes as active contributors to myelin pathology in CNS disease.
Authors
- Stacey Pedraza
- Eneritz Agirre (ORCID: https://orcid.org/0000-0002-5012-0305)
- Madeline H. Cooper (ORCID: https://orcid.org/0000-0001-5698-5150)
- Petra Kukanja (ORCID: https://orcid.org/0000-0003-1228-5923)
- Ugne Klibaite (ORCID: https://orcid.org/0000-0001-9729-7258)
- Gonçalo Castelo‐Branco (ORCID: https://orcid.org/0000-0003-2247-9393)
- Mark Terasaki (ORCID: https://orcid.org/0000-0003-4964-9401)
- J. Bradley Zuchero (ORCID: https://orcid.org/0000-0002-4706-2538)
- Jayakrishnan Gopakumar (ORCID: https://orcid.org/0000-0003-3895-8188)
- Mattia Zaghi (ORCID: https://orcid.org/0000-0002-3643-5407)
- Michael Schoof (ORCID: https://orcid.org/0000-0003-3531-5232)
- Anna Williams (ORCID: https://orcid.org/0000-0002-6329-382X)
- Lawrence Steinman (ORCID: https://orcid.org/0000-0002-2437-2250)
- Nadine Bestard-Cuche (ORCID: https://orcid.org/0000-0003-3381-2390)
- Danielle M. Jorgens (ORCID: https://orcid.org/0000-0002-7143-0118)
- John J. Perrino (ORCID: https://orcid.org/0000-0003-0825-3160)
- Caldwell M. Bridges (ORCID: https://orcid.org/0000-0002-5622-7402)
- Maya K. Weigel (ORCID: https://orcid.org/0000-0003-0557-5172)
- Peggy Pui-Kay Ho (ORCID: https://orcid.org/0000-0002-6848-318X)
- George Tilton-Low (ORCID: https://orcid.org/0009-0000-8345-6879)
- Graham Jones
- Veronika V. Rodriguez
Institutions
- Marine Biological Laboratory (US)
- Science for Life Laboratory (SE)
- Karolinska Institutet (SE)
- MRC Centre for Regenerative Medicine (GB)
- Stanford Medicine (US)
- University of California, Berkeley (US)
- Stanford University (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-11-04
- DOI
- https://doi.org/10.64898/2026.11.03.764025
- Primary Topic
- Multiple Sclerosis Research Studies
- Type
- preprint