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

eLife | 2018

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.

Pubmed ID: 30311906 RIS Download

Associated grants

  • Agency: Université Paris Descartes, International
    Id: BioSPC program
  • Agency: European Commission, International
    Id: ERA-NET 643578-EURO-CDG2
  • Agency: European Commission, International
    Id: ERA-NET E-Rare-3
  • Agency: Fondation pour la Recherche Médicale, International
    Id: FRM-DEQ20160334938
  • Agency: Agence Nationale de la Recherche, International
    Id: ANR-16-CE12- 0005-01

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