Functions of Neuroglycan C, Which Specific to the Central Nervous System, and its Application to the Neural Regeneration

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Neuroglycan C(NGC), a membrane-spanning chondroitin sulfate proteoglycan(PG) that is predominantly expressed in the brain. To clarify the role of NGC in development of the brain, we planned to generate NGC gene mutant mice, which show abnormal expressions of NGC by conditionally-targeted disruption of the NGC-gene. Now, we have gotten three strains of mice ; NGC-knockout mice that are completely deficient in all splice variants, NGC-knockdown mice in which the expression of NGC are down-regulated in various regions of the brain, and NGC-knockin mice that express NGC in non-PG form due to a mutation(S123A) at the chondroitin sulfate(CS) chain binding site. All these mice were viable and fertile. Histochemical studies showed that these mice did not show macroscopic abnormalities in gross brain anatomy. NGC-knockout mice displayed an obvious abnormality in Morris water maze test as well as NGC-knockdown mice, suggesting. that NGC is involved in learning and/or memory.We have reported that three transcripts for NGC splice variants(NGC-I, -II, and -III) exist in the human brain. In the present project, we discovered a new transcript for another splice variant, NGC-IV. We could demonstrate by Western blotting that NGC-IV was really expressed in some neuronal cells in the hippocampus, which is related to learning and/or memory. Furthermore, we demonstrated that NGC-V, another new transcript of NGC, was expressed in the hippocampus.NGC is a typical part-time PG that changes its structure from a PG form to a non-PG form during the development of the brain. Modification of the NGC core protein with CS is also differently regulated depending on cell types. However,the regulatory mechanism for the addition of the CS chain to NGC core protein is not known at present. In culture cells, we demonstrated that GRP78, one of stress-response proteins, might be related to CS glycosylation of NGC.