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High N-glycan multiplicity is critical for neuronal adhesion and sensitizes the developing cerebellum to N-glycosylation defect

Proper brain development relies highly on protein N-glycosylation to sustain neuronal migration, axon guidance and synaptic physiology. Impairing the N-glycosylation pathway at early steps produces broad neurological symptoms identified in congenital disorders of glycosylation. However, little is kn...

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Main Authors: Medina-Cano, Daniel (Author) , Ucuncu, Ekin (Author) , Nguyen, Lam Son (Author) , Nicouleau, Michael (Author) , Lipecka, Joanna (Author) , Bizot, Jean-Charles (Author) , Thiel, Christian (Author) , Foulquier, François (Author) , Lefort, Nathalie (Author) , Faivre-Sarrailh, Catherine (Author) , Colleaux, Laurence (Author) , Guerrera, Ida Chiara (Author) , Cantagrel, Vincent (Author)
Format: Article (Journal)
Language:English
Published: 12 October 2018
In: eLife
Year: 2018, Volume: 7
ISSN:2050-084X
DOI:10.7554/eLife.38309
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.7554/eLife.38309
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Author Notes:Daniel Medina-Cano, Ekin Ucuncu, Lam Son Nguyen, Michael Nicouleau, Joanna Lipecka, Jean-Charles Bizot, Christian Thiel, François Foulquier, Nathalie Lefort, Catherine Faivre-Sarrailh, Laurence Colleaux, Ida Chiara Guerrera, Vincent Cantagrel
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Summary:Proper brain development relies highly on protein N-glycosylation to sustain neuronal migration, axon guidance and synaptic physiology. Impairing the N-glycosylation pathway at early steps produces broad neurological symptoms identified in congenital disorders of glycosylation. However, little is known about the molecular mechanisms underlying these defects. We generated a cerebellum specific knockout mouse for Srd5a3, a gene involved in the initiation of N-glycosylation. In addition to motor coordination defects and abnormal granule cell development, Srd5a3 deletion causes mild N-glycosylation impairment without significantly altering ER homeostasis. Using proteomic approaches, we identified that Srd5a3 loss affects a subset of glycoproteins with high N-glycans multiplicity per protein and decreased protein abundance or N-glycosylation level. As IgSF-CAM adhesion proteins are critical for neuron adhesion and highly N-glycosylated, we observed impaired IgSF-CAM-mediated neurite outgrowth and axon guidance in Srd5a3 mutant cerebellum. Our results link high N-glycan multiplicity to fine-tuned neural cell adhesion during mammalian brain development.
Item Description:Gesehen am 25.03.2020
Physical Description:Online Resource
ISSN:2050-084X
DOI:10.7554/eLife.38309

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