RESTORATION OF SYNTHESIS OF SULFOGLUCURONYLGLYCOLIPIDS IN CEREBELLAR GRANULE NEURONS PROMOTES DEDIFFERENTIATION AND NEURITE OUTGROWTH

Sulfoglucuronyl carbohydrate (SGC) linked to the terminal moiety of ne olacto-oligosaccharides is expressed in several glycoproteins of the i mmunoglobulin superfamily involved in neural cell-cell recognition as well as in two sulfoglucuronylglycolipids (SGGLs) of the nervous syste m. SGGLs and SGC-containing glycoproteins are temporally and spatially regulated during development of the nervous system, In the cerebellum , the expression of SGC, particularly that of SGGLs, is biphasic, Seve ral studies have suggested that the initial rise and decline in the le vels of SGGLs and SGC-containing proteins correlated with the migratio n of granule neurons from the external granule cell layer to the inter nal granule cell layer and their subsequent maturation, whereas the la ter rise and continued expression of SGGLs in the adult was associated with their localization in the Purkinje neurons and their dendrites i n the molecular layer. Here it is shown by immunocytochemical methods that the expression of SGC declined progressively in granule neurons i solated from cerebella of increasing age, The decline in the expressio n of SGC in granule neurons was also shown with time in culture. These results correlated with the previously shown declining activity of th e regulatory enzyme lactosylceramide N-acetylglucosaminyltransferase ( GlcNAc-Tr) with age in vivo and in isolated granule neurons in culture , GlcNAc-Tr synthesizes a key precursor, lactotriosylceramide, involve d in the biosynthesis of SGGL-1. The downregulated synthesis of SGGLs in the mature granule neurons was shown by immunocytochemical and bioc hemical methods to be restored when a precursor, glucuronylneolactotet raosylceramide (GGL-1), which is beyond the GlcNAc-Tr step, was exogen ously provided to these cells, The biological effect of such restorati on of the synthesis of SGGLs in the mature granule neurons leads to ce ll aggregation and enhanced proliferation of neurites, amounting to de differentiation.