Neural and synaptic defects in slytherin, a zebrafish model for human congenital disorders of glycosylation

• Published in: PloS one Vol. 5; no. 10; p. e13743
• Main Authors: Song, Yuanquan, Willer, Jason R, Scherer, Paul C, Panzer, Jessica A, Kugath, Amy, Skordalakes, Emmanuel, Gregg, Ronald G, Willer, Gregory B, Balice-Gordon, Rita J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.10.2010; Public Library of Science (PLoS)
• Subjects: Amino Acid Sequence; Analysis; Animals; Biochemistry; Cloning; Congenital diseases; Congenital Disorders of Glycosylation - genetics; Danio rerio; Defects; Dehydration; Developmental Biology/Neurodevelopment; Disease Models, Animal; Drosophila; Enzymes; Freshwater; GDP-mannose; Gene mutation; Genetic disorders; Genomics; Genotype & phenotype; Glycoproteins; Glycosylation; Humans; Hydro-Lyases - genetics; Immunodeficiency; In Situ Hybridization; Insects; Kinases; Ligands; Mannose; Medicine; Mental disorders; Metabolism; Molecular biology; Molecular Sequence Data; Morphogenesis; Motility; Mutation; Mutation, Missense; Nervous System - metabolism; Neurogenesis; Neurological Disorders; Neuroscience/Neurodevelopment; Neurosciences; Neutrophils; Notch protein; Pathogenesis; Point mutation; Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Rodents; Sequence Homology, Amino Acid; Signaling; Synapses - metabolism; Synaptogenesis; Zebrafish; Kentucky; Pennsylvania
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0013743

Congenital disorder of glycosylation type IIc (CDG IIc) is characterized by mental retardation, slowed growth and severe immunodeficiency, attributed to the lack of fucosylated glycoproteins. While impaired Notch signaling has been implicated in some aspects of CDG IIc pathogenesis, the molecular and cellular mechanisms remain poorly understood. We have identified a zebrafish mutant slytherin (srn), which harbors a missense point mutation in GDP-mannose 4,6 dehydratase (GMDS), the rate-limiting enzyme in protein fucosylation, including that of Notch. Here we report that some of the mechanisms underlying the neural phenotypes in srn and in CGD IIc are Notch-dependent, while others are Notch-independent. We show, for the first time in a vertebrate in vivo, that defects in protein fucosylation leads to defects in neuronal differentiation, maintenance, axon branching, and synapse formation. Srn is thus a useful and important vertebrate model for human CDG IIc that has provided new insights into the neural phenotypes that are hallmarks of the human disorder and has also highlighted the role of protein fucosylation in neural development.