UC San Diego

Transcription factors play an essential role in organism development and homeostasis; and loss or impaired function of transcription factors has been implicated in a variety of developmental disorders and chronic diseases. Here, we show the transcription factor Ras Responsive Element Binding Protein 1 (RREB1) is essential for Purkinje cell survival in the mammalian brain. We identified a spontaneous mutation that results in hypomorphic loss of Rreb1 and leads to progressive Purkinje cell degeneration and ataxia in mice. ChIP-seq of RREB1 in wild-type cells and RNA-seq in wild-type and Rreb1-deficient Purkinje cells demonstrated RREB1 directly, positively regulates genes associated with the microtubule network and autophagy.Dysregulation of genes associated with the microtubule network lead to alterations in posttranslational modifications of tubulin and reduced dendritic branching in Purkinje cells. Altered expression of genes associated with autophagy lead to a reduction in autophagosomes and lysosomes, and the accumulation of P62- and Ubiquitin-positive inclusions. Interestingly, while this study demonstrates a role for RREB1 in the microtubule network and proteostasis in neurons, examination of RREB1 in HEK 293-T cells suggests it plays a different role in this cell type. Analysis of RREB1 ChIP-seq data from Purkinje cells and HEK 293-T cells identified an overlap in many target genes. Surprisingly, while RREB1 positively regulates these genes in Purkinje cells, it appears to negatively regulate these genes in HEK 293-T cells. Examination of autophagic flux in Rreb1 knockout cells demonstrated no significant difference between knockout cells and wild-type cells. Together, these studies demonstrate a novel and specific role for RREB1 in maintaining the microtubule network and proteostasis in mammalian neurons.