The primary goal of this research is to gain a better understanding of the mechanisms through which cellular interactions influence gene expression in the developing central nervous system. Bergmann glia cells in the mouse cerebellum express high levels of the enzyme, sn-glycerol-3-phosphate dehydrogenase (GPDH), beginning shortly after birth. Based largely on observations of GPDH expression in certain neurological mutant mice it appears that the characteristic pattern of GPDH expression in the Bergmann glia depends upon an early and sustained interaction between those cells and adjacent Prukinje neurons. This system, then, constitutes an appropriate model of a common but not well understood developmental phenomenon.
The specific aims of this proposal are: 1. To test the cell interaction hypothesis further by determining whether either of the mutants Lurcher or Purkinje cell degeneration, cause reduced glial GPDH levels through the intrinsic action of the genes within the glia. This will be accomplished by studying GPDH expression in chimeric mice where genetically marked mutant glial cells will be associated with normal Purkinje cells; 2. To obtain information concerning the nature of the cell interaction, i.e. cell contact mediated or diffusible factor mediated, the dimensions of the sphere of influence of individual Purkinje cells on GPDH expression in Bergmann glia will be examined. Regions of chimeric cerebellar cortex containing isolated Purkinje cells will be examined immunocytochemically in serial sections. The numbers of GPDH- positive Bergmann glia will be counted and their distances from the Purkinje cells measured.; and 3. To increase our understanding of the ultimate spatial realtionsips between clonally related cells and thereby, learn more about the process of cerebellar morphogenesis the genotype distribution of Bergmann glia in the chimeras relative to the distribution of Purkinje cells will be examined. By plotting the relative positions of Bergmann glia and Purkinje cells by genotype in a number of sections, one can determine whether the extent to which glia and Purkinje cells of like genotype cluster together is random or not.
| Fisher, M; Trimmer, P; Ruthel, G (1993) Bergmann glia require continuous association with Purkinje cells for normal phenotype expression. Glia 8:172-82 |
| Fisher, M (1991) Influence of grafted neurons on glial enzyme expression. Ann N Y Acad Sci 633:528-9 |
| Fisher, M (1990) Chimeric analysis of the site of Lurcher gene action with respect to glial enzyme expression. J Neurogenet 6:183-90 |
| Fisher, M; Mullen, R J (1988) Neuronal influence on glial enzyme expression: evidence from chimeric mouse cerebellum. Neuron 1:151-7 |
