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Making a brain: Without sugar, NCAM can't

Mice without functional polysialyltransferases (PST-negative) display disrupted midline crossing of axons in the posterior part of the corpus callosum.

A member of the immunoglobulin (Ig) superfamily, the neural cell adhesion molecule (NCAM) is a cell-surface glycoprotein that is modified with a unique sugar chain. Polysialyltransferase enzymes catalyze the addition of the anionic carbohydrate polysialic acid (polySia) to the fifth NCAM Ig domain. Polysialylated NCAM is involved in neurogenesis, axon outgrowth, migration and synaptic plasticity, and is implicated in neural development. Previous research has also shown that the loss of polysialyltransferase expression in mice causes brain defects and early death. Now Hildebrandt et al. have shown that the brain deficiencies correlate specifically with the amount of erroneously unpolysialylated NCAM. Reporting in Brain, the authors posit that loss of the blocking sugar chain allows NCAM to form inappropriate interactions during development, potentially explaining a link between NCAM and schizophrenia.

The adhesive and signaling properties of NCAM derive from homophilic interactions between the Ig domains of separate molecules and the regulated addition of polySia prevents these interactions sterically, masking NCAM function. The developmental brain abnormalities caused by deletion of two mouse polysialyltransferase genes, St8sialI and St8sialV, can be rescued by simultaneous ablation of NCAM expression, suggesting that polySia-free NCAM is responsible for the defects. Hildebrandt et al. analyzed mice with different combinations of wild-type and mutant Ncam, St8sialI and St8sialV alleles to explore how these translate into pathological morphology. In the wild-type mice, all NCAM was polysialylated at postnatal day 1, a developmental stage chosen because major brain fiber tracts are not yet fully developed. Where both polysialyltransferases were functionally absent, all NCAM was polySia-free. Mutation of one Ncam allele reduced the message by 50% and the total brain NCAM level by 30%. In combination with mutation of one or both alleles of each polysialyltransferase, a range of mice with varying levels of total and polySia-free NCAM was obtained.

Sections of brain were taken from 4- to 6-week-old mice to correlate morphology with these early NCAM levels. Major brain fiber tracts were measured, including, for example the corpus callosum, a bundle of axons below the cortex along which much of the inter-hemispheric brain communication is conducted. In mice without a functional polysialyltransferase, the corpus callosum was considerably shorter and had no midline-crossing fibers in the posterior section. The extent of this and other defects correlated linearly with the levels of polySia-free NCAM at postnatal day 1 and was unaffected by the presence or absence of additional, properly modified NCAM. The ability of polysialyltransferases to glycosylate NCAM is therefore essential for proper tract formation.

Schizophrenia is a complex disorder with a high level of heritability and has been linked to variations in the genes for human NCAM and polysialyltransferase. Disturbed cortical connections resembling those seen in the mice with high levels of polySia-free NCAM are also seen in schizophrenic patients. This study highlights the importance of coordinated glycosylation for proper brain development and proposes incomplete polysialylation of NCAM during development as a mechanism for predisposition to schizophrenia.

Author: Emma Leah