UC San Diego

The transcription factor Ras Responsive Element Binding Protein 1 (RREB1) was recently demonstrated as essential for Purkinje cell survival, and it positively regulates genes associated with the microtubule network and autophagy in the mammalian nervous system. We previously described a spontaneous mutation in NOD/ShiLtJ mice that leads to the hypomorphic loss of Rreb1 resulting in ataxia and the progressive loss of cerebellar Purkinje cells. Mutant Purkinje cells also contained p62-positive inclusions. Introducing the mutant allele onto the C57BL/6J (B6J) background resulted in increased cerebellar Purkinje cell degeneration, suggesting enhancing modifier genes are present in the B6J background. Here I show that B6J alleles are recessive. I also performed QTL mapping, which identified two potential locations for modifier genes on Chromosomes 4 and 14. Further characterization of these severely affected mice revealed that p62-positive inclusions occurred at an earlier age than those in Rreb1-deficient mice on the NOD background. Histological examination for additional phenotypic changes in other brain regions expressing Rreb1, such as the substantia nigra and the dentate gyrus, failed to reveal degeneration. These studies detail the modified phenotypes and point to candidate regions that might contribute to influencing Purkinje cell loss in Rreb1-deficient mice.