title: Sialylation regulates brain structure and function.
abstract: Every cell expresses a molecularly diverse surface glycan coat (glycocalyx) comprising its interface with its cellular environment. In vertebrates, the terminal sugars of the glycocalyx are often sialic acids, 9-carbon backbone anionic sugars implicated in intermolecular and intercellular interactions. The vertebrate brain is particularly enriched in sialic acid-containing glycolipids termed gangliosides. Human congenital disorders of ganglioside biosynthesis result in paraplegia, epilepsy, and intellectual disability. To better understand sialoglycan functions in the nervous system, we studied brain anatomy, histology, biochemistry, and behavior in mice with engineered mutations in St3gal2 and St3gal3, sialyltransferase genes responsible for terminal sialylation of gangliosides and some glycoproteins. St3gal2/3 double-null mice displayed dysmyelination marked by a 40% reduction in major myelin proteins, 30% fewer myelinated axons, a 33% decrease in myelin thickness, and molecular disruptions at nodes of Ranvier. In part, these changes may be due to dysregulation of ganglioside-mediated oligodendroglial precursor cell proliferation. Neuronal markers were also reduced up to 40%, and hippocampal neurons had smaller dendritic arbors. Young adult St3gal2/3 double-null mice displayed impaired motor coordination, disturbed gait, and profound cognitive disability. Comparisons among sialyltransferase mutant mice provide insights into the functional roles of brain gangliosides and sialoglycoproteins consistent with related human congenital disorders.
authors.affiliation: *Department of Pharmacology and Molecular Sciences, Department of Neurology, and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA; Brain Trauma Neuroprotection and Neurorestoration Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA; and International Center for Spinal Cord Injury, Hugo W. Moser Research Institute, Kennedy Krieger, Baltimore, Maryland, USA.
authors.forename: Seung-Wan
authors.initials: SW
authors.lastname: Yoo
authors.affiliation: *Department of Pharmacology and Molecular Sciences, Department of Neurology, and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA; Brain Trauma Neuroprotection and Neurorestoration Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA; and International Center for Spinal Cord Injury, Hugo W. Moser Research Institute, Kennedy Krieger, Baltimore, Maryland, USA.
authors.forename: Mary G
authors.initials: MG
authors.lastname: Motari
authors.affiliation: *Department of Pharmacology and Molecular Sciences, Department of Neurology, and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA; Brain Trauma Neuroprotection and Neurorestoration Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA; and International Center for Spinal Cord Injury, Hugo W. Moser Research Institute, Kennedy Krieger, Baltimore, Maryland, USA.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Susuki
authors.affiliation: *Department of Pharmacology and Molecular Sciences, Department of Neurology, and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA; Brain Trauma Neuroprotection and Neurorestoration Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA; and International Center for Spinal Cord Injury, Hugo W. Moser Research Institute, Kennedy Krieger, Baltimore, Maryland, USA.
authors.forename: Jillian
authors.initials: J
authors.lastname: Prendergast
authors.affiliation: *Department of Pharmacology and Molecular Sciences, Department of Neurology, and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA; Brain Trauma Neuroprotection and Neurorestoration Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA; and International Center for Spinal Cord Injury, Hugo W. Moser Research Institute, Kennedy Krieger, Baltimore, Maryland, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mountney
authors.affiliation: *Department of Pharmacology and Molecular Sciences, Department of Neurology, and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA; Brain Trauma Neuroprotection and Neurorestoration Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA; and International Center for Spinal Cord Injury, Hugo W. Moser Research Institute, Kennedy Krieger, Baltimore, Maryland, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Hurtado
authors.affiliation: *Department of Pharmacology and Molecular Sciences, Department of Neurology, and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA; Brain Trauma Neuroprotection and Neurorestoration Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA; and International Center for Spinal Cord Injury, Hugo W. Moser Research Institute, Kennedy Krieger, Baltimore, Maryland, USA schnaar@jhu.edu.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Schnaar
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000033:anatomy & histology* / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005732:Gangliosides / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D017628:Microglia / Q000378:metabolism; D023421:Models, Animal; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D012794:Sialic Acids / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000378:metabolism; D012799:Sialyltransferases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
chemical_list: D005732:Gangliosides; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D012794:Sialic Acids; D012795:Sialoglycoproteins; D012799:Sialyltransferases; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
keywords: animal models; behavior; gangliosides; myelin; oligodendrocyte precursor cells
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