Fyn tyrosine kinase regulates oligodendroglial cell development but is not required for morphological differentiation of oligodendrocytes

Sperber, Brian R.; McMorris, F. Arthur

doi:10.1002/1097-4547(20010215)63:4<303::aid-jnr1024>3.0.co;2-a

Cited by 91 publications

(47 citation statements)

References 61 publications

(86 reference statements)

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“…1C). We utilized a previously described method (70) for the staging of oligodendrocyte differentiation based on morphological features ( Fig. 2A) to further assess the stages of differentiated cells after agnoprotein expression.…”

Section: Resultsmentioning

confidence: 99%

JC Virus Agnoprotein Inhibits In Vitro Differentiation of Oligodendrocytes and Promotes Apoptosis

Merabova

Kaniowska

Kaminski

et al. 2008

J Virol

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Productive infection of oligodendrocytes, which are responsible for the formation of myelin sheath in the central nervous system, with the human neurotropic virus JC virus (JCV) causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). In addition to encoding T antigen and the capsid proteins, which are produced at the early and late phases of the infection cycle, respectively, JCV encodes a small regulatory protein named agnoprotein that is important for successful completion of the virus life cycle. Here we used bipotential CG-4 cells to examine the impact of agnoprotein on oligodendrocyte differentiation and survival in the absence of JCV lytic infection. We demonstrate that the expression of agnoprotein delayed the formation of complex outgrowth networks of the cells during oligodendrocyte differentiation. These alterations were accompanied by high levels of DNA damage, induction of proapoptotic proteins, and suppression of prosurvival signaling. Accordingly, apoptosis was significantly increased upon the induction of CG-4 cells toward differentiation in cells expressing agnoprotein. These observations provide the first evidence for the possible involvement of agnoprotein, independent from its role in viral replication, in a series of biological events that may contribute to the pathological features seen in PML lesions.First exposure to the human polyomavirus JC virus (JCV) commonly occurs during childhood and results in a subclinical outcome. Reactivation of the initially latent virus in individuals with impaired immune systems results in the development of the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML) (9,31,35). PML manifests clinically with signs of neurological deficits of various degrees, including weakness, visual deficits, and cognitive abnormalities. PML is mainly associated with advanced human immunodeficiency virus (HIV)-induced diseases and AIDS (8, 9), lymphoproliferative or myeloproliferative diseases, malignancies, and rheumatic disorders treated with corticosteroids and cytotoxic drugs (1,16,25,34,39,52,58,71,75,77). Recently, PML has also been diagnosed in patients with multiple sclerosis and Crohn's disease receiving natalizumab (37,40,42,74), a humanized monoclonal antibody that binds to the ␣4 subunit of ␣4␤1 and ␣4␤7 integrins and inhibits the trafficking of leukocytes across the blood-brain barrier.The histological hallmarks of white matter from PML patients include the appearance of oligodendrocytes with enlarged hyperchromatic nuclei that contain inclusion bodies shaped by crystalline arrays of JCV particles and astrocytes with bizarre nuclei and mitotic figures (21, 35). The presence of virions has also been demonstrated among lamellae of the myelin sheath of a viable axon (47). In cell culture systems, JCV efficiently infects primary cultures of human brain containing oligodendrocytes and astrocytes. Recent studies have shown that JCV can infect multipotential human central nervous system progenitor cells isolated fro...

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Section: Resultsmentioning

confidence: 99%

JC Virus Agnoprotein Inhibits In Vitro Differentiation of Oligodendrocytes and Promotes Apoptosis

Merabova

Kaniowska

Kaminski

et al. 2008

J Virol

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“…Fyn is a key molecule in OLG differentiation and myelination (Osterhout et al, 1999;Sperber and McMorris, 2001;Umemori et al, 1994). This molecule belongs to the Src (Rous sarcoma) family of kinases and is associated with cell migration, proliferation, differentiation, adhesion, apoptosis and cytoskeletal rearrangements (Osterhout et al, 1999).…”

Section: Initial Axon-glial Contactmentioning

confidence: 85%

Rafts in oligodendrocytes: Evidence and structure–function relationship

Gielen

Baron

vandeVen

et al. 2006

Glia

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“…Axl ϩ/Ϫ , Rse ϩ/Ϫ , and Akt ϩ/Ϫ heterozygotes were mated to obtain Axl Ϫ/Ϫ , Rse Ϫ/Ϫ , and Akt1 Ϫ/Ϫ homozygotes and WT littermates. Oligodendrocyte cultures were established from postnatal day 1 WT, homozygous knock-out mice by a modification of previously established protocols (Knapp et al, 1987;Armstrong, 1998;Sperber and McMorris, 2001). Mice were decapitated, and the cerebral hemispheres were removed aseptically.…”

Section: Methodsmentioning

confidence: 99%

Gas6/Axl Signaling Activates the Phosphatidylinositol 3-Kinase/Akt1 Survival Pathway to Protect Oligodendrocytes from Tumor Necrosis Factorα-Induced Apoptosis

Shankar¹,

O’Guin²,

Kim³

et al. 2006

J. Neurosci.

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Growth arrest-specific protein 6 (gas6) activity is mediated through the receptor tyrosine kinase family members Axl, Rse, and Mer, all of which are expressed in human oligodendrocytes. In this study, we examined whether recombinant human (rh) gas6 protects oligodendrocytes from growth factor (insulin) withdrawal or tumor necrosis factor-␣ (TNF␣) cytotoxicity. In addition, we examined whether the effect was caspase-dependent, which receptor mediated the protective effect, and whether survival required Akt1 activation. Oligodendrocyte viability was assessed by O4 staining and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling. Addition of rhgas6 to insulin-depleted cultures resulted in a significant increase in oligodendrocyte viability. Rhgas6 and caspase inhibitors also reduced active caspase-3 immunoreactivity relative to TNF␣-only-treated cultures. In cultures treated with TNF␣ (100 ng/ml), the oligodendrocyte survival rate was 18% compared with cultures treated with TNF␣ and rhgas6 ( Akt1Ϫ/Ϫ oligodendrocytes. Oligodendrocyte cultures established from wild-type and Rse Ϫ/Ϫ mice, but not from Axl Ϫ/Ϫ mice, were also protected from TNF␣-induced cell death when maintained in rhgas6. We conclude that gas6 signaling through the Axl receptor and the PI3 kinase/Akt1 survival pathway protects oligodendrocytes from growth factor withdrawal and TNF␣-mediated cell death.

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Fyn tyrosine kinase regulates oligodendroglial cell development but is not required for morphological differentiation of oligodendrocytes

Cited by 91 publications

References 61 publications

JC Virus Agnoprotein Inhibits In Vitro Differentiation of Oligodendrocytes and Promotes Apoptosis

JC Virus Agnoprotein Inhibits In Vitro Differentiation of Oligodendrocytes and Promotes Apoptosis

Rafts in oligodendrocytes: Evidence and structure–function relationship

Gas6/Axl Signaling Activates the Phosphatidylinositol 3-Kinase/Akt1 Survival Pathway to Protect Oligodendrocytes from Tumor Necrosis Factorα-Induced Apoptosis

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