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

Abstract : 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.
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https://hal-amu.archives-ouvertes.fr/hal-01963631
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Submitted on : Friday, December 21, 2018 - 2:24:13 PM
Last modification on : Thursday, April 9, 2020 - 11:58:24 AM
Long-term archiving on: : Friday, March 22, 2019 - 5:52:43 PM

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Daniel Medina-Cano, Ekin Ucuncu, Lam Nguyen, Michael Nicouleau, Joanna Lipecka, et al.. High N-glycan multiplicity is critical for neuronal adhesion and sensitizes the developing cerebellum to N-glycosylation defect. eLife, eLife Sciences Publication, 2018, 7, ⟨10.7554/eLife.38309⟩. ⟨hal-01963631⟩

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