Signaling from Integrins to Fyn to Rho Family GTPases Regulates Morphologic Differentiation of Oligodendrocytes
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Differentiation of oligodendrocyte progenitor cells requires activation of the Src family kinase Fyn. The signals that are upstream and downstream of Fyn in oligodendrocytes remain essentially unknown. Here we show that extracellular matrix engagement regulates the morphology of oligodendrocytes and activates Fyn. Infection of primary oligodendrocyte cultures with recombinant adenovirus revealed that expression of Fyn or its downstream target p190RhoGAP induced process extension. This phenotypic change was not observed when kinase-inactive Fyn or GAP-defective p190 mutants were expressed. Because Rho family proteins are regulated by p190, we monitored the effects of introducing dominant-negative (DN) or constitutively activated (CA) versions of Rho, Rac1, or Cdc42 into primary oligodendrocyte cultures. Expression of DN Rho, CA Rac1, or CA Cdc42 induced outgrowth of oligodendrocyte processes, whereas introduction of CA Rho, DN Rac1, or DN cdc42 inhibited oligodendrocyte differentiation, indicating that Rho and Cdc42-Rac1 exert opposing effects on oligodendrocyte differentiation. Direct measurement of Rho family activity revealed that RhoA was downregulated, and Cdc42 and Rac1 were upregulated during differentiation of primary oligodendrocytes. Moreover, inhibition of integrin engagement or of Fyn activation blocked activation of Rac1 and cdc42 as well as myelin basic protein expression. Taken together, these results suggest a linear signal transduction pathway of integrin-Fyn-Rho family GTPases that controls morphologic differentiation of oligodendrocytes.
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Signalling pathways downstream of activin receptor activation include Rac/Cdc42 GTPases, Akt, and mTOR, all of which have been previously implicated in positively regulating oligodendrocyte differentiation and/or myelination.
“In accordance with our finding, signalling pathways downstream of activin receptor activation include Rac/Cdc42 GTPases, Akt, and mammalian target of rapamycin (mTOR), all of which have been previously implicated in positively regulating oligodendrocyte differentiation and/or myelination38-41.”
From M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination (2013) · cites this paper as [38]
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References 51 · Cited by 255
- Authors
- Liang, X., Draghi, N. A., & Resh, M. D.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Resh, Marilyn D.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2004-08-11
- Volume
- 24
- Issue
- 32
- Pages
- 7140-7149
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6729178
- OpenAlex
- W2015602829
- Cited by
- 255
- References
- 51
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 10 · 2023: 11 · 2022: 19 · 2021: 14 · 2020: 7 · 2019: 9 · 2018: 6 · 2017: 2 · 2016: 12 · 2015: 15 · 2014: 11 · 2013: 20 · 2012: 6
- FWCI
- 3.40
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Multiple Sclerosis Society
- Multiple Sclerosis Society
- National Institutes of Health
- National Cancer Institute (CA96582, R01CA096582)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- oligodendrocyte differentiation, oligodendrocyte precursor cells, Fyn, Src family kinases, integrins, Rho GTPases, p190RhoGAP, Rac1, Cdc42, RhoA, myelin basic protein, oligodendrocyte morphology, signal transduction
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, DNA-Binding Proteins, Extracellular Matrix, Nuclear Proteins, Oligodendroglia, Proto-Oncogene Proteins, Repressor Proteins, Stem Cells, Transfection, Signal Transduction, Down-Regulation, Integrins, Rats, Sprague-Dawley, src-Family Kinases, COS Cells, Guanine Nucleotide Exchange Factors, rho GTP-Binding Proteins, cdc42 GTP-Binding Protein, rac1 GTP-Binding Protein, Proto-Oncogene Proteins c-fyn, Rats
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