FGF signaling induces disease-associated oligodendrocyte states and drives myelin pathology
- 1Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA
Abstract
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.
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BibTeX
@misc{weigel2026signaling,
title = {{FGF signaling induces disease-associated oligodendrocyte states and drives myelin pathology}},
author = {M. K. Weigel and M. H. Cooper and M. Zaghi and J. Gopakumar and C. M. Bridges and P. P. Ho and M. Schoof and U. Klibaite and S. Pedraza and E. Agirre and G. Tilton-Low and N. Bestard-Cuche and P. Kukanja and V. V. Rodriguez and G. Jones and J. J. Perrino and D. M. Jorgens and M. R. Terasaki and A. Williams and L. Steinman and G. Castelo-Branco and J. B. Zuchero},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.03.764025},
url = {https://www.biorxiv.org/content/10.64898/2026.11.03.764025v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - FGF signaling induces disease-associated oligodendrocyte states and drives myelin pathology
AU - M. K. Weigel
AU - M. H. Cooper
AU - M. Zaghi
AU - J. Gopakumar
AU - C. M. Bridges
AU - P. P. Ho
AU - M. Schoof
AU - U. Klibaite
AU - S. Pedraza
AU - E. Agirre
AU - G. Tilton-Low
AU - N. Bestard-Cuche
AU - P. Kukanja
AU - V. V. Rodriguez
AU - G. Jones
AU - J. J. Perrino
AU - D. M. Jorgens
AU - M. R. Terasaki
AU - A. Williams
AU - L. Steinman
AU - G. Castelo-Branco
AU - J. B. Zuchero
PY - 2026
DA - 2026/11/03
PB - bioRxiv
DO - 10.64898/2026.11.03.764025
UR - https://www.biorxiv.org/content/10.64898/2026.11.03.764025v1
AB - 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.
ER -