Interacting Genes Control Glycerol-3-Phosphate Dehydrogenase Expression in Developing Cerebellum of the Mouse

The cerebellum of BALB/cJ mice has approximately 2.5 times as much glycerol-3-phosphate dehydrogenase (GPDH) as that of C57BL/6J mice. This difference in enzyme levels, which positively correlates with similar differences in the levels of hybridizable GPDH mRNA, is controlled by at least two unlinked regulatory loci and the structural gene, Gdc-1, located on chromosome 15. These regulatory loci, which act predominantly during the second and third weeks of postnatal cerebellar development and differentiation, have been separated from each other in the CXB recombinant inbred strains of mice. One regulatory locus, Gdcr-1, although unlinked to the structural gene, has an allele in BALB/c mice that preferentially enhances expression of the BALB/c structural allele at Gdc-1. The other locus, Gdcr-2, which may or may not be single, enhances GPDH expression at Gdc-1 irrespective of the allele present, as is commonly observed for loci acting from a distance. Measurements of GPDH mRNA in the recombinant inbred mice suggest that these regulatory genes act by modulating mRNA levels. Accordingly, the regulation of GPDH expression in the cerebellum of mice depends on a complex interaction of unlinked regulatory elements with regulatory elements near the structural gene. Furthermore, since the Gdc-1 locus is expressed in virtually every tissue of the mouse except blood and since the observed genetic variation is restricted to the cerebellum, it is likely that other tissues will have their own distinctive genetic mechanisms for modulating Gdc-1 expression.