Small Maf Compound Mutants Display Central Nervous System Neuronal Degeneration, Aberrant Transcription, and Bach Protein Mislocalization Coincident with Myoclonus and Abnormal Startle Response

Abstract

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 cellautonomous neuronal deficiencies that lead to profound neurological defects.

Genetic Evidence that Small Maf Proteins Are Essential for the Activation of Antioxidant Response Element-Dependent Genes

“…Since several neurodegenerative disorders are suspected to result from a dysregulated oxidative stress response, we analyzed the expression of ARE-dependent genes in the central nervous systems of these symptomatic mutant mice. These studies showed that the heme oxygenase 1 gene (HO-1) was induced in G0K1 compound mutant animals, whereas many other ARE-dependent genes were not significantly affected (16). We also found that Bach proteins failed to accumulate in neuronal nuclei in the G0K1 central nervous system, which could explain the observed HO-1 transcriptional derepression (16,42).…”

“…Although mafF Ϫ/Ϫ (F0) and mafK Ϫ/Ϫ (K0) mice displayed no apparent mutant phenotypes, mafG-null mutant mice displayed mild thrombocytopenia accompanied by a late-onset neurological disorder (39). The neurological abnormality was exacerbated in mafG Ϫ/Ϫ ::mafK ϩ/Ϫ (G0K1) compound mutant mice, suggesting that MafG and MafK share compensatory functions in the central nervous system (16). Since several neurodegenerative disorders are suspected to result from a dysregulated oxidative stress response, we analyzed the expression of ARE-dependent genes in the central nervous systems of these symptomatic mutant mice.…”

“…These studies showed that the heme oxygenase 1 gene (HO-1) was induced in G0K1 compound mutant animals, whereas many other ARE-dependent genes were not significantly affected (16). We also found that Bach proteins failed to accumulate in neuronal nuclei in the G0K1 central nervous system, which could explain the observed HO-1 transcriptional derepression (16,42). However, these studies did not resolve whether or not the small Maf proteins collaboratively, with a CNC partner, contribute to the activation of ARE-dependent genes.…”

Nrf2 Transcriptionally Activates the mafG Gene through an Antioxidant Response Element

“…2 Therefore, we concluded that small Maf proteins act cooperatively with Nrf2 to activate the transcription of these genes. In contrast, HO-1 transcription is derepressed in small maf compound mutant mice, similarly to the bach1-null mutant (16), suggesting that small Maf proteins are also important for collaboratively repressing HO-1. In this way, we genetically confirmed that small Maf proteins act as required cofactors in both positive and negative MARE-dependent regulation of gene transcription.…”

“…However, it is also possible that small Maf proteins heterodimerize with Bach1 to form a transcriptional repressor. The Bach1-MafG heterodimer may repress mafG gene transcription through mafG Ic-ARE in the same way as it represses HO-1 gene expression (9,16). The contribution of Bach1 proteins to the regulation of mafG is under investigation.…”