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Fringe modulation of Jagged1-induced Notch signaling requires the action of beta 4galactosyltransferase-1.

ABSTRACT: Fringe modulates Notch signaling resulting in the establishment of compartmental boundaries in developing organisms. Fringe is a beta 3N-acetylglucosaminyltransferase (beta 3GlcNAcT) that transfers GlcNAc to O-fucose in epidermal growth factor-like repeats of Notch. Here we use five different Chinese hamster ovary cell glycosylation mutants to identify a key aspect of the mechanism of fringe action. Although the beta 3GlcNAcT activity of manic or lunatic fringe is shown to be necessary for inhibition of Jagged1-induced Notch signaling in a coculture assay, it is not sufficient. Fringe fails to inhibit Notch signaling if the disaccharide generated by fringe action, GlcNAc beta 3Fuc, is not elongated. The trisaccharide, Gal beta 4GlcNAc beta 3Fuc, is the minimal O-fucose glycan to support fringe modulation of Notch signaling. Of six beta 4galactosyltransferases (beta 4GalT) in Chinese hamster ovary cells, only beta 4GalT-1 is required to add Gal to GlcNAc beta 3Fuc, identifying beta 4GalT-1 as a new modulator of Notch signaling.

SUBMITTER: Chen J

PROVIDER: S-EPMC61107 | biostudies-literature | 2001 Nov

REPOSITORIES: biostudies-literature

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Fringe modulation of Jagged1-induced Notch signaling requires the action of beta 4galactosyltransferase-1.

Chen J J Moloney D J DJ Stanley P P

Proceedings of the National Academy of Sciences of the United States of America 20011113 24

Fringe modulates Notch signaling resulting in the establishment of compartmental boundaries in developing organisms. Fringe is a beta 3N-acetylglucosaminyltransferase (beta 3GlcNAcT) that transfers GlcNAc to O-fucose in epidermal growth factor-like repeats of Notch. Here we use five different Chinese hamster ovary cell glycosylation mutants to identify a key aspect of the mechanism of fringe action. Although the beta 3GlcNAcT activity of manic or lunatic fringe is shown to be necessary for inhib ...[more]

PMID: 11707585

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Project description:Duchenne muscular dystrophy (DMD) is a severe X-linked recessive muscle disorder caused by mutations in the dystrophin gene. Nonetheless, secondary processes involving perturbation of muscle regeneration probably exacerbate disease progression, resulting in the fatal loss of muscle in DMD patients. A dysfunction of undifferentiated myogenic cells is the most likely cause for the reduction of regenerative capacity of muscle. To clarify molecular mechanisms in perturbation of the regenerative capacity of DMD muscle, we have established several NCAM (CD56)-positive immortalized human dystrophic and non-dystrophic myogenic cell lines from DMD and healthy muscles. A pro-inflammatory cytokine, IL-1?, promoted cell cycle progression of non-dystrophic myogenic cells but not DMD myogenic cells. In contrast, IL-1? upregulated the Notch ligand Jagged1 gene in DMD myogenic cells but not in non-dystrophic myogenic cells. Knockdown of Jagged1 in DMD myogenic cells restored the IL-1?-promoted cell cycle progression. Conversely, enforced expression of Jagged1-blocked IL-1? promoted proliferation of non-dystrophic myogenic cells. In addition, IL-1? prevented myogenic differentiation of DMD myogenic cells depending on Jagged1 but not of non-dystrophic myogenic cells. These results demonstrate that Jagged1 induced by IL-1? in DMD myogenic cells modified the action of IL-1? and reduced the ability to proliferate and differentiate. IL-1? induced Jagged1 gene expression may be a feedback response to excess stimulation with this cytokine because high IL-1? (200-1000 pg/ml) induced Jagged1 gene expression even in non-dystrophic myogenic cells. DMD myogenic cells are likely to acquire the susceptibility of the Jagged1 gene to IL-1? under the microcircumstances in DMD muscles. The present results suggest that Jagged1 induced by IL-1? plays a crucial role in the loss of muscle regeneration capacity of DMD muscles. The IL-1?/Jagged1 pathway may be a new therapeutic target to ameliorate exacerbation of muscular dystrophy in a dystrophin-independent manner.

Dataset Information

Fringe modulation of Jagged1-induced Notch signaling requires the action of beta 4galactosyltransferase-1.

Publications

Fringe modulation of Jagged1-induced Notch signaling requires the action of beta 4galactosyltransferase-1.

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