The long term goal of this research is to understand the cellular mechanisms that establish the topographically organized regions of the vertebrate brain. Topographic organization involves spatial and temporal patterns of neuroblast and axon migration. A search for the molecules that might be involved in these processes, using immunofluorescent screens on rat embryo neural tissue and antibodies raised against fetal rat retina, has resulted in the identification of an alkali sensitive ganglioside antigen recognized by a monoclonal IgM antibody (JONES). JONES binding studies show that this antigen 1) has a highly spatially and temporally regulated expression in the neural tube; 2) disappears rapidly from most brain regions at birth and has a continued expression only in the outer plexiform layer of the retina and around the Purkinje cells of the cerebellum and 3) in the late fetus and neonate is distributed in a dorsal to ventral gradient across the retina and is present in the regions of the eye and brain where retinal axons are known to grow. The developmental profile of stained regions suggest that in the fetal and neonate brain the JONES binding ganglioside is associated with the migration (and not the proliferation) of select populations of cells and cell processes. This hypothesis will be examined through combined immunocytochemical and tritiated thymidine studies of the topographic and cytoarchitectonic differentiation of the retina, the diencephalic and mesencephalic retinal pathway and the cerebellum in embryonic and postnatal brains. In addition a number of projects will develop the assays and probes necessary for future antibody blocking experiments that will test whether the JONES binding ganglioside, or a molecule(s) similar to it, is crucial to the selective migration of differentiating cell and axon populations. Thus these studies will establish a retinal cell to tectum binding assay, a retinal neurite migration assay, and a cerebellar neuroblast migration assay. They will also apply biochemical and immunological techniques to obtain: active monovalent fragments of the JONES antibody, a varient JONES hybridoma cell line that has switched to secreting an IgG antibody and a new battery of monoclonal antibodies raised specifically against early neural gangliosides. The evaluation of the role of this developmentally regulated neural ganglioside will increase our understanding of early brain morphogenesis. In addition, since gangliosides have been implicated in many processes of neural growth and repair our studies may prove important to finding a solution to the clinical problems resulting from the poor regenerative ability of the more mature human CNS.
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| Bonafede, D M; Macala, L J; Constantine-Paton, M et al. (1989) Isolation and characterization of ganglioside 9-O-acetyl-GD3 from bovine buttermilk. Lipids 24:680-4 |
