ST8SIA2 promotes oligodendrocyte differentiation and the integrity of myelin and axons

Abstract

ST8SIA2 is a polysialyltransferase that attaches polysialic acid to the glycoproteins NCAM1 and CADM1. Polysialylation is involved in brain development and plasticity. ST8SIA2 is a schizophrenia candidate gene, and St8sia2 −/− mice exhibit schizophrenia‐like behavior. We sought to identify new pathological consequences of ST8SIA2 deficiency. Our proteomic analysis suggested myelin impairment in St8sia2 −/− mice. Histological and immune staining together with Western blot revealed that the onset of myelination was not delayed in St8sia2 −/− mice, but the content of myelin was lower. Ultrastructure analysis of the corpus callosum showed thinner myelin sheaths, smaller and irregularly shaped axons, and white matter lesions in adult St8sia2 −/− mice. Then we evaluated oligodendrocyte differentiation in vivo and in vitro. Fewer OLIG2+ cells in the cortex and corpus callosum, together with the higher percentage of undifferentiated oligodenroglia in St8sia2 −/− mice suggested an impairment in oligodendrocyte generation. Experiment on primary cultures of oligodendrocyte precursor cells (OPCs) confirmed a cell‐autonomous effect of ST8SIA2 in oligodendroglia, and demonstrated that OPC to oligodendrocyte transition is inhibited in St8sia2 −/− mice. Concluding, ST8SIA2‐mediated polysialylation influences on oligodendrocyte differentiation, and oligodendrocyte deficits in St8sia2 mice are a possible cause of the demyelination and degeneration of axons, resembling nerve fiber alterations in schizophrenia. GLIA 2016;65:34–49

Amygdala GluN2B-NMDAR dysfunction is critical in abnormal aggression of neurodevelopmental origin induced by St8sia2 deficiency

“…In addition, although to our knowledge there was no previous study detailing the impact of St8sia2 deficiency on neonatal amygdala development, several studies have revealed alterations in other brain regions occurring after birth in St8sia2−/− mice. The reported alterations include a decrease in GABA neurons in the prefrontal cortex observed at P1, but not E16.5; [81] deficits in olfactory interneurons only seen at P5; [82] and a decrease in myelination observed from P15 onwards [83]. More generally, polysialylation is an essential process involved in the migration and clustering of neural and glial precursors [23,81,84], axonal growth and fasciculation [85], synapse formation and plasticity [86,87], and myelination [83].…”

Bad wrap: Myelin and myelin plasticity in health and disease

“…ST8SIA2 knock out mouse models exhibit delayed myelination and decreased myelin content, including thinner sheaths, irregularly shaped axons, and increased white matter lesions in adulthood. ST8SIA2 knockout mice also exhibit increases in the number of immature oligodendrocytes in the cortex and the corpus callosum that may imply a blockade of OPC differentiation to myelinating oligodendrocytes (Szewczyk et al, ).…”

Astrocytic glutamine synthetase is expressed in the neuronal somatic layers and down‐regulated proportionally to neuronal loss in the human epileptic hippocampus

“…Cells with nuclear Olig2 expression were negative for GS or GFAP. Extranuclear signal in the Olig2-channel occurred in both lowDeg and highDeg samples, in the presence and absence of primary antibodies, and was mainly interpreted as unspecific secondary antibody binding (Supporting Information,Figures S4 and S5, white circles),(Rhee et al, 2009;Szewczyk et al, 2017). However, atypical cytosolic/extranuclear expression of Olig2 as a possible consequence of the disease cannot be excluded.…”