Expression of the APC tumor suppressor protein in oligodendroglia

Bhat, Ratan V.; Axt, Karen J.; Fosnaugh, Jennifer S.; Smith, Kelly J.; Johnson, Karen A.; Hill, David E.; Kinzler, Kenneth W.; Baraban, Jay M.

doi:10.1002/(sici)1098-1136(199606)17:2<169::aid-glia8>3.3.co;2-g

Cited by 24 publications

(25 citation statements)

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“…sc-575; 1:1,000), rabbit antibody against Calbindin D-28 (Swant CB38; 1:1,000), mouse monoclonal antibody against IP3R1 (NeuroMab, clone L24-18; 1:200) (34), mouse monoclonal antibody against APC (EMD Millipore, cat no. OP80; 1:200) (35), and mouse monoclonal antibody against neuronspecific nuclear protein (NeuN; EMD Millipore, cat no. MAB377; 1:500).…”

Section: Methodsmentioning

confidence: 89%

Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency

Spassieva

Liu

et al. 2016

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

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Sphingolipids exhibit extreme functional and chemical diversity that is in part determined by their hydrophobic moiety, ceramide. In mammals, the fatty acyl chain length variation of ceramides is determined by six (dihydro)ceramide synthase (CerS) isoforms. Previously, we and others showed that mutations in the major neuron-specific CerS1, which synthesizes 18-carbon fatty acyl (C 18 ) ceramide, cause elevation of long-chain base (LCB) substrates and decrease in C 18 ceramide and derivatives in the brain, leading to neurodegeneration in mice and myoclonus epilepsy with dementia in humans. Whether LCB elevation or C 18 ceramide reduction leads to neurodegeneration is unclear. Here, we ectopically expressed CerS2, a nonneuronal CerS producing C 22 -C 24 ceramides, in neurons of Cers1-deficient mice. Surprisingly, the Cers1 mutant pathology was almost completely suppressed. Because CerS2 cannot replenish C 18 ceramide, the rescue is likely a result of LCB reduction. Consistent with this hypothesis, we found that only LCBs, the substrates common for all of the CerS isoforms, but not ceramides and complex sphingolipids, were restored to the wild-type levels in the Cers2-rescued Cers1 mutant mouse brains. Furthermore, LCBs induced neurite fragmentation in cultured neurons at concentrations corresponding to the elevated levels in the CerS1-deficient brain. The strong association of LCB levels with neuronal survival both in vivo and in vitro suggests high-level accumulation of LCBs is a possible underlying cause of the CerS1 deficiency-induced neuronal death.sphingolipid | ceramide synthase | ceramide | long-chain base | neurodegeneration S phingolipids carry out essential functions in eukaryotes (1).The hydrophobic moiety of sphingolipids, called ceramide, is a fatty acylated long-chain base (LCB). LCBs can differ in their degree of saturation (e.g., sphingosine vs. dihydrosphingosine/ sphinganine) or hydroxylation (e.g., sphingosine vs. phytosphingosine) (2). LCBs and their phosphorylated derivatives are potent signaling molecules (3). Moreover, accumulation of aberrant deoxy-LCBs has recently been linked to hereditary sensory and autonomic neuropathy type 1 and taxane-induced peripheral neuropathy (4-6). Very high concentrations (100 μM) of regular LCBs are also toxic to cultured neurons (7,8). In addition, intoxication with fumonisin B1, a fungal ceramide synthase inhibitor causing elevation of LCBs and reduction of ceramides, leads to neural tube and neurological defects in humans and cattle (9). However, whether accumulation of regular LCBs in vivo or LCB treatment at physiologically relevant concentrations in vitro causes neuron death or damage has not been thoroughly investigated.The fatty acyl chain of ceramide can also vary in chain lengths, saturation, and hydroxylation (2). Emerging evidence suggests specific functions for different ceramide species. For instance, ceramide with a C 18 fatty acyl chain (C 18 ceramide) has been suggested to cause apoptosis in certain cancer cells, whereas ceramide with a C 16 ...

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Section: Methodsmentioning

confidence: 89%

Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency

Spassieva

Liu

et al. 2016

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

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“…Antibodies were used at the following dilutions: anti-myelin basic protein (MBP) monoclonal antibody (mAb) (mouse IgG1, 1:50; Euromedex, Souffelweyersheim, France), anti-glial fibrillary acidic protein (GFAP) (mouse mAb, 1:200) (Jacque et al, 1986), A2B5 mAb (mouse IgM, 1:5; American Type Culture Collection, Manassas, VA), O4 mAb (mouse IgM, 1:10) (Sommer and Schachner, 1982), anti-proteolipid protein (PLP) (rat mAb clone AA3, 1:10) (Yamamura et al, 1991), anti-␤-galactosidase (rabbit polyclonal antibody, 1:1000; Organon Technika, West Chester, PA), antigalactosylceramide (GalC) (mouse mAb IgG3, 1:10) (Ranscht et al, 1982), rat anti-NG2 antibody (1:400) (Diers-Fenger et al, 2001), antiadenomatous polyposis coli (APC) antibody (mouse mAb, 1:50; VWR International, Fontenay Sous Bois, France) (Bhat et al, 1996,), anti-MAC1 antibody (rat mAb IgG2b, 1:100; Ozyme, St. Quentin en Yvelines, France), anti-F4 -80 antibody (rat mAb IgG2b, 1:200; Serotec, Cergy, France), anti-MAP2 antibody (mouse mAb IgG1, 1:100; Sigma, St. Louis, MO), and SMI31/32 antibodies (mouse mAb IgG1, 1:1000; Sternberger Monoclonals, Lutherville, MD). Rabbit anti-rat Edg8/S1P5 antiserum was generated against the extreme C-terminal 12 amino acids of the rat Edg8/S1P5 receptor sequence (CTANRTLVPDATD; the first cysteine is not in the sequence but was added as a linker to attach the peptide to the KLH carrier for immunization).…”

Section: Methodsmentioning

confidence: 99%

“…3C,D). However, even within the strongly Edg8/S1P5-positive myelinated tracts, the anti-Edg8/S1P5 Ab failed to label APCpositive oligodendrocyte cell bodies [APC is an established marker of the cell body of mature oligodendrocytes (Bhat et al, 1996)] (Fig. 3 E, F ).…”

Section: Pattern Of Expression Of Edg8/s1p5 In Postnatal Brainmentioning

confidence: 99%

Edg8/S1P5: An Oligodendroglial Receptor with Dual Function on Process Retraction and Cell Survival

Jaillard

Harrison²,

Stankoff³

et al. 2005

J. Neurosci.

313

276

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Endothelial differentiation gene (Edg) proteins are G-protein-coupled receptors activated by lysophospholipid mediators: sphingosine-1-phosphate (S1P) or lysophosphatidic acid. We show that in the CNS, expression of Edg8/S1P5, a high-affinity S1P receptor, is restricted to oligodendrocytes and expressed throughout development from the immature stages to the mature myelin-forming cell. S1P activation of Edg8/S1P5 on O4-positive pre-oligodendrocytes induced process retraction via a Rho kinase/collapsin response-mediated protein signaling pathway, whereas no retraction was elicited by S1P on these cells derived from Edg8/S1P5-deficient mice. Edg8/S1P5-mediated process retraction was restricted to immature cells and was no longer observed at later developmental stages. In contrast, S1P activation promoted the survival of mature oligodendrocytes but not of pre-oligodendrocytes. The S1P-induced survival of mature oligodendrocytes was mediated through a pertussis toxin-sensitive, Akt-dependent pathway. Our data demonstrate that Edg8/S1P5 activation on oligodendroglial cells modulates two distinct functional pathways mediating either process retraction or cell survival and that these effects depend on the developmental stage of the cell.

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“…Primary antibodies were as follows: P2X 1 , P2X 2 , P2X 4 , and P2X 7 (1-2 g/ml; Alomone Labs, Jerusalem, Israel), P2X 3 (1 g/ml; Chemicon, Temecula, CA), P2X 5 and P2X 6 (1:1000; Santa Cruz Biotechnology, Santa Cruz, CA), myelin basic protein (MBP) (1 g/ml; Sternberger Monoclonals, Berkeley, CA), and adenomatous polyposis coli antigen (APC) (1 g/ml; Calbiochem, Barcelona, Spain), an oligodendrocyte marker (Bhat et al, 1996). Controls in oligodendrocyte cultures as well as in tissue sections were performed by either omitting the primary antibody or preadsorbing the primary antibody with an excess of the corresponding peptide (50 g/ml final concentration).…”

Section: ϩmentioning

confidence: 99%

“…To localize the expression of P2X receptor subunits in oligodendrocytes, we performed Western blot and doubleimmunofluorescence labeling of cultured myelin basic proteinpositive oligodendrocytes (MBP ϩ cells), as well as rat optic nerve and spinal cord sections with subunit-specific antibodies to P2X receptors and with the oligodendrocyte marker APC (Bhat et al, 1996). Immunoblotting revealed that the 75 kDa band corresponding to the P2X 7 receptor is present in the rat optic nerve as well as in cultured oligodendrocytes from this structure (Fig.…”

Section: B) and Bzatp-induced Currents In Ca 2ϩmentioning

confidence: 99%

P2X₇Receptor Blockade Prevents ATP Excitotoxicity in Oligodendrocytes and Ameliorates Experimental Autoimmune Encephalomyelitis

Matute¹,

Torre²,

et al. 2007

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Oligodendrocyte death and demyelination are hallmarks of multiple sclerosis (MS).Here we show that ATP signaling can trigger oligodendrocyte excitotoxicity via activation of calcium-permeable P2X 7 purinergic receptors expressed by these cells. Sustained activation of P2X 7 receptors in vivo causes lesions that are reminiscent of the major features of MS plaques, i.e., demyelination, oligodendrocyte death, and axonal damage. In addition, treatment with P2X 7 antagonists of chronic experimental autoimmune encephalomyelitis (EAE), a model of MS, reduces demyelination and ameliorates the associated neurological symptoms. Together, these results indicate that ATP can kill oligodendrocytes via P2X 7 activation and that this cell death process contributes to EAE. Importantly, P2X 7 expression is elevated in normal-appearing axon tracts in MS patients, suggesting that signaling through this receptor in oligodendrocytes may be enhanced in this disease. Thus, P2X 7 receptor antagonists may be beneficial for the treatment of MS.

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Expression of the APC tumor suppressor protein in oligodendroglia

Cited by 24 publications

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Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency

Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency

Edg8/S1P5: An Oligodendroglial Receptor with Dual Function on Process Retraction and Cell Survival

P2X₇Receptor Blockade Prevents ATP Excitotoxicity in Oligodendrocytes and Ameliorates Experimental Autoimmune Encephalomyelitis

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Expression of the APC tumor suppressor protein in oligodendroglia

Cited by 24 publications

References 0 publications

Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency

Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency

Edg8/S1P5: An Oligodendroglial Receptor with Dual Function on Process Retraction and Cell Survival

P2X7Receptor Blockade Prevents ATP Excitotoxicity in Oligodendrocytes and Ameliorates Experimental Autoimmune Encephalomyelitis

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P2X₇Receptor Blockade Prevents ATP Excitotoxicity in Oligodendrocytes and Ameliorates Experimental Autoimmune Encephalomyelitis