Small Maf compound mutants display central nervous system neuronal degeneration, aberrant transcription, and Bach protein mislocalization coincident with myoclonus and abnormal startle response.

The small Maf proteins form heterodimers with CNC and Bach family proteins to elicit transcriptional responses from Maf recognition elements (MAREs). We previously reported germ line-targeted deficiencies in mafG plus mafK compound mutant mice. The most prominent mutant phenotype was a progressive maf dosage-dependent neuromuscular dysfunction. However, there has been no previous report regarding the effects of altered small-maf gene expression on neurological dysfunction. We show here that MafG and MafK are expressed in discrete central nervous system (CNS) neurons and that mafG::mafK compound mutants display neuronal degeneration coincident with surprisingly selective MARE-dependent transcriptional abnormalities. The CNS morphological changes are concurrent with the onset of a neurological disorder in the mutants, and the behavioral changes are accompanied by reduced glycine receptor subunit accumulation. Bach/small Maf heterodimers, which normally generate transcriptional repressors, were significantly underrepresented in nuclear extracts prepared from maf mutant brains, and Bach proteins fail to accumulate normally in nuclei. Thus compound mafG::mafK mutants develop age- and maf gene dosage-dependent cell-autonomous neuronal deficiencies that lead to profound neurological defects.