A Unique Role for Fyn in CNS Myelination

Overview

Journal J Neurosci

Specialty Neurology

Date 2001 Mar 14

PMID 11245687

Citations 78

Authors

B R Sperber

M J Engleka

P Gadue

A C Peterson

P L Stein

S S Scherer

F A McMorris

Affiliations

Soon will be listed here.

Abstract

We analyzed the role of Fyn tyrosine kinase in CNS myelination by using fyn(-/-) null mutant mice, which express no Fyn protein. We found a severe myelin deficit in forebrain at all ages from 14 d to 1 year. The deficit was maximal at 1 month of age and was similar regardless of mouse strain background or whether it was determined by bulk isolation of myelin or by quantitation of myelin basic protein. To determine the cellular basis of the myelin deficit, we counted oligodendrocytes in tissue sections of mice expressing oligodendrocyte-targeted beta-galactosidase, and we used light and electron microscopy to examine the number and morphology of myelinated fibers and size of myelinated CNS structures. All of these parameters were reduced in fyn(-/-) mice. Unexpectedly, there were regional differences in the myelin deficit; in contrast to forebrain, fyn(-/-) cervical spinal cord exhibited no reduction in myelin content, number of oligodendrocytes, or number of myelinated fibers, nor was myelination delayed developmentally. We found that oligodendrocytes express Src, but there was no significant reduction of myelin content in null mutants lacking the Fyn-related kinases Src, Yes, or Lyn. Finally, we investigated the molecular features of Fyn that are required for myelination and found that a single amino acid substitution, which abolishes the tyrosine kinase activity of Fyn, resulted in a myelin deficit as great as that observed in the complete absence of Fyn protein. These results demonstrate that Fyn plays a unique role in myelination, one that requires its kinase activity.

Citing Articles

Impacts of hnRNP A1 Splicing Inhibition on the Brain Remyelination Proteome.

Brandao-Teles C, Carregari V, Reis-de-Oliveira G, Smith B, Chaves Y, Sousa Santos A J Neurochem. 2025; 169(1):e16304.

PMID: 39840781 PMC: 11752419. DOI: 10.1111/jnc.16304.

Fyn, an important molecule in the brain, is a potential therapeutic target for brain tumours.

Xu C, Tang Y, Lu X, Chen R Front Pharmacol. 2024; 15:1485919.

PMID: 39697541 PMC: 11652172. DOI: 10.3389/fphar.2024.1485919.

Outside-in signaling through the major histocompatibility complex class-I cytoplasmic tail modulates glutamate receptor expression in neurons.

Eyford B, Lazarczyk M, Choi K, Varghese M, Arora H, Kari S Sci Rep. 2023; 13(1):13079.

PMID: 37567897 PMC: 10421907. DOI: 10.1038/s41598-023-38663-z.

Unraveling the Mechanisms of Clinical Drugs-Induced Neural Tube Defects Based on Network Pharmacology and Molecular Docking Analysis.

Guan Z, Liang Y, Wang X, Zhu Z, Yang A, Li S Neurochem Res. 2022; 47(12):3709-3722.

PMID: 35960485 DOI: 10.1007/s11064-022-03717-7.

Comprehensive Atlas of the Myelin Basic Protein Interaction Landscape.

Smirnova E, Rakitina T, Ziganshin R, Arapidi G, Saratov G, Kudriaeva A Biomolecules. 2021; 11(11).

PMID: 34827627 PMC: 8615356. DOI: 10.3390/biom11111628.

References

Bjartmar C . Morphological heterogeneity of cultured spinal and cerebral rat oligodendrocytes. Neurosci Lett. 1998; 247(2-3):91-4. DOI: 10.1016/s0304-3940(98)00264-x. View

Katsuta H, Tsuji S, Niho Y, Kurosaki T, Kitamura D . Lyn-mediated down-regulation of B cell antigen receptor signaling: inhibition of protein kinase C activation by Lyn in a kinase-independent fashion. J Immunol. 1998; 160(4):1547-51. View

Sperber B, McMorris F . Fyn tyrosine kinase regulates oligodendroglial cell development but is not required for morphological differentiation of oligodendrocytes. J Neurosci Res. 2001; 63(4):303-12. DOI: 10.1002/1097-4547(20010215)63:4<303::AID-JNR1024>3.0.CO;2-A. View

Xu H, Littman D . A kinase-independent function of Lck in potentiating antigen-specific T cell activation. Cell. 1993; 74(4):633-43. DOI: 10.1016/0092-8674(93)90511-n. View

Osterhout D, WOLVEN A, Wolf R, Resh M, Chao M . Morphological differentiation of oligodendrocytes requires activation of Fyn tyrosine kinase. J Cell Biol. 1999; 145(6):1209-18. PMC: 2133143. DOI: 10.1083/jcb.145.6.1209. View

Thomas S, Brugge J . Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol. 1997; 13:513-609. DOI: 10.1146/annurev.cellbio.13.1.513. View

Fruttiger M, Karlsson L, Hall A, Abramsson A, Calver A, BOSTROM H . Defective oligodendrocyte development and severe hypomyelination in PDGF-A knockout mice. Development. 1999; 126(3):457-67. DOI: 10.1242/dev.126.3.457. View

Schwartzberg P, Xing L, Hoffmann O, Lowell C, Garrett L, Boyce B . Rescue of osteoclast function by transgenic expression of kinase-deficient Src in src-/- mutant mice. Genes Dev. 1997; 11(21):2835-44. PMC: 316651. DOI: 10.1101/gad.11.21.2835. View

Raible D, McMorris F . Induction of oligodendrocyte differentiation by activators of adenylate cyclase. J Neurosci Res. 1990; 27(1):43-6. DOI: 10.1002/jnr.490270107. View

10.

McMorris F, Miller S, Pleasure D, Abramsky O . Expression of biochemical properties of oligodendrocytes in oligodendrocyte x glioma cell hybrids proliferating in vitro. Exp Cell Res. 1981; 133(2):395-404. DOI: 10.1016/0014-4827(81)90332-3. View

11.

Kramer E, Klein C, Koch T, Boytinck M, Trotter J . Compartmentation of Fyn kinase with glycosylphosphatidylinositol-anchored molecules in oligodendrocytes facilitates kinase activation during myelination. J Biol Chem. 1999; 274(41):29042-9. DOI: 10.1074/jbc.274.41.29042. View

12.

Spassky N, Olivier C, Perez-Villegas E, Goujet-Zalc C, Martinez S, Thomas J . Single or multiple oligodendroglial lineages: a controversy. Glia. 2000; 29(2):143-8. View

13.

Thomas S, Soriano P, Imamoto A . Specific and redundant roles of Src and Fyn in organizing the cytoskeleton. Nature. 1995; 376(6537):267-71. DOI: 10.1038/376267a0. View

14.

Miyakawa T, Yagi T, Watanabe S, Niki H . Increased fearfulness of Fyn tyrosine kinase deficient mice. Brain Res Mol Brain Res. 1994; 27(1):179-82. DOI: 10.1016/0169-328x(94)90201-1. View

15.

McCarthy K, de Vellis J . Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol. 1980; 85(3):890-902. PMC: 2111442. DOI: 10.1083/jcb.85.3.890. View

16.

Umemori H, Sato S, Yagi T, Aizawa S, Yamamoto T . Initial events of myelination involve Fyn tyrosine kinase signalling. Nature. 1994; 367(6463):572-6. DOI: 10.1038/367572a0. View

17.

Sommer I, Schachner M . Monoclonal antibodies (O1 to O4) to oligodendrocyte cell surfaces: an immunocytological study in the central nervous system. Dev Biol. 1981; 83(2):311-27. DOI: 10.1016/0012-1606(81)90477-2. View

18.

Spassky N, Goujet-Zalc C, Parmantier E, Olivier C, Martinez S, Ivanova A . Multiple restricted origin of oligodendrocytes. J Neurosci. 1998; 18(20):8331-43. PMC: 6792828. View

19.

Stein P, Lee H, Rich S, Soriano P . pp59fyn mutant mice display differential signaling in thymocytes and peripheral T cells. Cell. 1992; 70(5):741-50. DOI: 10.1016/0092-8674(92)90308-y. View

20.

Soriano P, Montgomery C, Geske R, Bradley A . Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell. 1991; 64(4):693-702. DOI: 10.1016/0092-8674(91)90499-o. View