A Unique Role for Fyn in CNS Myelination

Sperber, Brian R.; Boyle-Walsh, Eilis; Engleka, Mark J.; Gadue, Paul; Peterson, Alan C.; Stein, Paul L.; Scherer, Steven S.; McMorris, F. Arthur

doi:10.1523/jneurosci.21-06-02039.2001

Cited by 168 publications

(157 citation statements)

References 35 publications

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“…Among these SFKs, Fyn plays a unique role in myelination, because myelin deficits are only found in Fyn Ϫ/Ϫ mice and not in Lyn Ϫ/Ϫ or Src Ϫ/Ϫ mice (9). As shown in Fig.…”

Section: Resultsmentioning

confidence: 91%

“…The siRNA-mediated silencing of PTP␣ in the rat CG4 OPC cell line results in impaired differentiation to OLs as evidenced by the prolonged maintenance of a high population of A2B5-positive population of progenitor cells, the inhibition of process extension, and the reduced expression of the maturation marker CNPase that is localized to cell bodies and processes. Oligosphere-derived OPCs isolated from PTP␣ Ϫ/Ϫ mouse embryos likewise exhibit an OL differentiation defect as deter- Fyn is activated during OPC differentiation, and this is critical for morphological differentiation, maturation, and CNS myelination (9,10,25,59). Several upstream molecules stimulate Fyn activity in this process, including the ligand-receptor interactions of extracellular matrix components like vitronectin and fibronectin with ␤1 integrins, laminin 2 binding to ␣6␤1 integrin, and the laminin family member netrin 1 and its receptor Dcc (12)(13)(14).…”

Section: Discussionmentioning

confidence: 99%

“…Although mice null for the SFKs Src, Yes, or Lyn do not exhibit defects in CNS myelination, mice with mutant Fyn or lacking Fyn exhibit hypomyelination (8,9). In vitro studies have linked Fyn activation or inhibition to several stimuli that, respectively, induce or inhibit OL differentiation and maturation.…”

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confidence: 99%

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Protein-tyrosine Phosphatase α Acts as an Upstream Regulator of Fyn Signaling to Promote Oligodendrocyte Differentiation and Myelination

Wang

Xiao

et al. 2009

Journal of Biological Chemistry

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The tyrosine kinase Fyn plays a key role in oligodendrocyte differentiation and myelination in the central nervous system, but the molecules responsible for regulating Fyn activation in these processes remain poorly defined. Here we show that receptor-like protein-tyrosine phosphatase ␣ (PTP␣) is an important positive regulator of Fyn activation and signaling that is required for the differentiation of oligodendrocyte progenitor cells (OPCs). PTP␣ is expressed in OPCs and is up-regulated during differentiation. We used two model systems to investigate the role of PTP␣ in OPC differentiation: the rat CG4 cell line where PTP␣ expression was silenced by small interfering RNA, and oligosphere-derived primary OPCs isolated from wild-type and PTP␣-null mouse embryos. In both cell systems, the ablation of PTP␣ inhibited differentiation and morphological changes that accompany this process. Although Fyn was activated upon induction of differentiation, the level of activation was severely reduced in cells lacking PTP␣, as was the activation of Fyn effector molecules focal adhesion kinase, Rac1, and Cdc42, and inactivation of Rho. Interestingly, another downstream effector of Fyn, p190RhoGAP, which is responsible for Rho inactivation during differentiation, was not affected by PTP␣ ablation. In vivo studies revealed defective myelination in the PTP␣ ؊/؊ mouse brain. Together, our findings demonstrate that PTP␣ is a critical regulator of Fyn activation and of specific Fyn signaling events during differentiation, and is essential for promoting OPC differentiation and central nervous system myelination.Myelination is an essential feature of the vertebrate nervous system. The myelin sheath provides electrical insulation to axons and facilitates transmission of nerve impulses. Other important roles of myelin are to contribute to neuronal survival and development, as well as neurotransmission and synaptic activity (1). Deficiencies in myelination during development, or demyelination that can occur following injury or in diseases such as multiple sclerosis, lead to neurological disorders (2-4).The formation of the highly specialized multilamellar myelin sheath by oligodendrocytes (OLs) 3 in the CNS occurs early in development, following proliferation and migration of oligodendrocyte progenitor cells (OPCs) to their final axonal targets (5). The molecular mechanisms that regulate OPC differentiation and OL maturation and myelination remain poorly understood. Consistent with the physical juxtaposition of axons and enwrapping oligodendroglia, axonal signals have been identified that influence OPC differentiation and/or myelination, such the axonal ligands Jagged1 and contactin that engage the glial receptor Notch (6, 7). Other signals, such as those described below that are provided by components of the extracellular matrix or the presence or absence of growth factors, are also important in these processes.The Src family tyrosine kinase (SFK) Fyn is an essential participant and central coordinator of OL differentiation, maturatio...

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“…Among these SFKs, Fyn plays a unique role in myelination, because myelin deficits are only found in Fyn Ϫ/Ϫ mice and not in Lyn Ϫ/Ϫ or Src Ϫ/Ϫ mice (9). As shown in Fig.…”

Section: Resultsmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Protein-tyrosine Phosphatase α Acts as an Upstream Regulator of Fyn Signaling to Promote Oligodendrocyte Differentiation and Myelination

Wang

Xiao

et al. 2009

Journal of Biological Chemistry

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“…Analysis of this sublist, with special regard to genes involved in OL differentiation (24), OPC self-renewal (25,26), differentiation of NSCs to OPCs (27), OPC plasticity (10), or NSC self-renewal (11,12,28), revealed that eight of the most highly down-regulated genes upon treatment with TSA are associated with the differentiation of OPCs to OLs (Table 1). Interestingly, this group exhibited expression profiles nearly identical to those of BMP-2-treated OPCs and included proteins involved in myelin formation (MBP, MAG, PLP, OMG, and CNPase) (24) as well as other factors that promote the transition of OPCs to OLs (Nkx2.2, Sox10, and Fyn) (24,29,30). The data indicate that the down-regulation of OL-specific gene expression is a common feature of BMP-2-and HDAC-mediated OPC plasticity.…”

Section: -L)mentioning

confidence: 99%

Inhibition of histone deacetylase activity induces developmental plasticity in oligodendrocyte precursor cells

Lyssiotis

Walker

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

116

103

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Recently, it was demonstrated that lineage-committed oligodendrocyte precursor cells (OPCs) can be converted to multipotent neural stem-like cells, capable of generating both neurons and glia after exposure to bone morphogenetic proteins. In an effort to understand and control the developmental plasticity of OPCs, we developed a high-throughput screen to identify novel chemical inducers of OPC reprogramming. Using this system, we discovered that inhibition of histone deacetylase (HDAC) activity in OPCs acts as a priming event in the induction of developmental plasticity, thereby expanding the differentiation potential to include the neuronal lineage. This conversion was found to be mediated, in part, through reactivation of sox2 and was highly reproducible at the clonal level. Further, genome-wide expression analysis demonstrated that HDAC inhibitor treatment activated sox2 and 12 other genes that identify or maintain the neural stem cell state while simultaneously silencing a large group of oligodendrocyte lineage-specific genes. This series of experiments demonstrates that global histone acetylation, induced by HDAC inhibition, can partially reverse the lineage restriction of OPCs, thereby inducing developmental plasticity.cell-based screen ͉ neural stem cells ͉ Sox2

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“…In support of this, it is worth noting that Fyn-knockout mice show CNS region-specific deficiencies in myelination, with spinal cord myelination appearing normal while forebrain myelination is impaired. 23 Thus, in addition to or besides activating Fyn, PTPα may negatively regulate other downstream elements that are positively involved in axonal ensheathment. Precisely how the absence of PTPα alters the balance among Fyn, Notch, and other pathways in oligodendrocytes during myelinogenesis, leading to an over-ensheathment of axons, remains to be explored.…”

Section: Methodsmentioning

confidence: 99%