Expression and function of the protein tyrosine phosphatase SHP-1 in oligodendrocytes

Massa, Paul T.; Saha, Sucharita; Wu, Chunchi; Jarosinski, Keith W.

doi:10.1002/(sici)1098-1136(20000215)29:4<376::aid-glia8>3.3.co;2-j

Cited by 8 publications

(13 citation statements)

References 22 publications

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“…Mixed glial cultures were produced from brains of 8-day-old mice as described previously [20]. Astrocyte-enriched cultures were produced as described previously [21].…”

Section: Glial Culturesmentioning

confidence: 99%

Induction of IL-33 expression and activity in central nervous system glia

Hudson

Christophi

Gruber

et al. 2008

Journal of Leukocyte Biology

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186

177

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IL-33 is a novel member of the IL-1 cytokine family and a potent inducer of type 2 immunity, as mast cells and Th2 CD4+ T cells respond to IL-33 with the induction of type 2 cytokines such as IL-13. IL-33 mRNA levels are extremely high in the CNS, and CNS glia possess both subunits of the IL-33R, yet whether IL-33 is produced by and affects CNS glia has not been studied. Here, we demonstrate that pathogen-associated molecular patterns (PAMPs) significantly increase IL-33 mRNA and protein expression in CNS glia. Interestingly, IL-33 was localized to the nucleus of astrocytes. Further, CNS glial and astrocyte-enriched cultures treated with a PAMP followed by an ATP pulse had significantly higher levels of supernatant IL-1beta and IL-33 than cultures receiving any single treatment (PAMP or ATP). Supernatants from PAMP + ATP-treated glia induced the secretion of IL-6, IL-13, and MCP-1 from the MC/9 mast cell line in a manner similar to exogenous recombinant IL-33. Further, IL-33 levels and activity were increased in the brains of mice infected with the neurotropic virus Theiler's murine encephalomyelitis virus. IL-33 also had direct effects on CNS glia, as IL-33 induced various innate immune effectors in CNS glia, and this induction was greatly amplified by IL-33-stimulated mast cells. In conclusion, these results implicate IL-33-producing astrocytes as a potentially critical regulator of innate immune responses in the CNS.

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“…Mixed glial cultures were produced from brains of 8-day-old mice as described previously [20]. Astrocyte-enriched cultures were produced as described previously [21].…”

Section: Glial Culturesmentioning

confidence: 99%

Induction of IL-33 expression and activity in central nervous system glia

Hudson

Christophi

Gruber

et al. 2008

Journal of Leukocyte Biology

Self Cite

186

177

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“…Loss of SHP-1 by null mutation, as in motheaten (me/me) mice, results in a number of hematopoietic abnormalities leading to increased inflammation, oxidative stress, and systemic autoimmune disease (Green and Shultz, 1975;Lyons et al, 2003;Shultz and Green, 1976;Sidman et al, 1978). We and others have demonstrated that oligodendrocytes of SHP-1-deficient mice express less mature myelin proteins and exhibit dysmyelination compared with their wild-type littermates (Massa et al, 2000(Massa et al, , 2004Massa and Wu, 1998;Wishcamper et al, 2001). However, the mechanisms by which oligodendrocyte pathology and aberrant myelin gene expression are affected by SHP-1 deficiency are not known.…”

Section: Introductionmentioning

confidence: 95%

The control of reactive oxygen species production by SHP-1 in oligodendrocytes

Gruber

LaRocca

Minchenberg

et al. 2015

Glia

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We have previously described reduced myelination and corresponding myelin basic protein (MBP) expression in the CNS of Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) deficient motheaten (me/me) mice compared to normal littermate controls. Deficiency in myelin and MBP expression in both brains and spinal cords of motheaten mice correlated with reduced MBP mRNA expression levels in vivo and in purified oligodendrocytes in vitro. Therefore, SHP-1 activity appears to be a critical regulator of oligodendrocyte gene expression and function. Consistent with this role, the present studies demonstrate that oligodendrocytes of motheaten mice and SHP-1 depleted N20.1 cells produce higher levels of reactive oxygen species (ROS) and exhibit corresponding markers of increased oxidative stress. In agreement with these findings, we demonstrate increased production of ROS coincides with ROS-induced signaling pathways known to affect myelin gene expression in oligodendrocytes. Antioxidant treatment of SHP-1-deficient oligodendrocytes reversed the pathological changes in these cells with increased myelin protein gene expression and decreased expression of nuclear factor (erythroid-2)–related factor 2 (Nrf2) responsive gene, heme oxygenase-1 (HO-1). Furthermore, we demonstrate that SHP-1 is expressed in human white matter oligodendrocytes and there is a subset of multiple sclerosis (MS) subjects that demonstrate a deficiency of SHP-1 in normal appearing white matter (NAWM). These studies reveal critical pathways controlled by SHP-1 in oligodendrocytes that relate to susceptibility of SHP-1-deficient mice to both developmental defects in myelination and to inflammatory demyelinating diseases.

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“…SHP-1 is a protein tyrosine phosphatase with two SH2 domains, which acts as a crucial negative regulator of cytokine signaling, inflammatory gene expression, and demyelination in central nervous system via STAT1, STAT3, and STAT6 [36][37][38][39]. Mice genetically lacking in SHP-1 (motheaten mice) display myelin deficiency, which may be mediated by increased inflammatory mediators in the CNS [40,41]. Christophil et al [42] established a role for SHP-1 in MS.…”

Section: Multiple Sclerosismentioning

confidence: 99%

Lentiviral Vector-Mediated Gene Transfer and RNA Silencing Technology in Neuronal Dysfunctions

Dreyer

2010

Mol Biotechnol

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Lentiviral-mediated gene transfer in vivo or in cultured mammalian neurons can be used to address a wide variety of biological questions, to design animals models for specific neurodegenerative pathologies, or to test potential therapeutic approaches in a variety of brain disorders. Lentiviruses can infect non-dividing cells, thereby allowing stable gene transfer in post-mitotic cells such as mature neurons. An important contribution has been the use of inducible vectors: the same animal can thus be used repeatedly in the doxycycline-on or -off state, providing a powerful mean for assessing the function of a gene candidate in a disorder within a specific neuronal circuit. Furthermore, lentivirus vectors provide a unique tool to integrate siRNA expression constructs with the aim to locally knockdown expression of a specific gene, enabling to assess the function of a gene in a very specific neuronal pathway. Lentiviral vector-mediated delivery of short hairpin RNA results in persistent knockdown of gene expression in the brain. Therefore, the use of lentiviruses for stable expression of siRNA in brain is a powerful aid to probe gene functions in vivo and for gene therapy of diseases of the central nervous system. In this chapter I review the applications of lentivirus-mediated gene transfer in the investigation of specific gene candidates involved in major brain disorders and neurodegenerative processes. Major applications have been in polyglutamine disorders, such as synucleinopathies and Parkinson's disease, or in investigating gene function in Huntington's disease, dystonia, or muscular dystrophy. Recently, lentivirus gene transfer has been an invaluable tool for evaluation of gene function in behavioral disorders such as drug addiction and attention-deficit hyperactivity disorder or in learning and cognition.

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Expression and function of the protein tyrosine phosphatase SHP-1 in oligodendrocytes

Cited by 8 publications

References 22 publications

Induction of IL-33 expression and activity in central nervous system glia

Induction of IL-33 expression and activity in central nervous system glia

The control of reactive oxygen species production by SHP-1 in oligodendrocytes

Lentiviral Vector-Mediated Gene Transfer and RNA Silencing Technology in Neuronal Dysfunctions

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