Estrogen-related Receptor Alpha (ERRα) is Required for PGC-1α-dependent Gene Expression in the Mouse Brain

•ERR binding sites are enriched in the promoter region of PGC-1α-responsive genes.•ERRα antagonism impedes the ability of PGC-1α to upregulate genes in vitro.•ERRα and PGC-1α are colocalized in parvalbumin-expressing interneurons.•ERRα deletion leads to reductions in PGC-1α-dependent transcripts in...

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Veröffentlicht in:Neuroscience 2021-12, Vol.479, p.70-90
Hauptverfasser: McMeekin, L.J., Joyce, K.L., Jenkins, L.M., Bohannon, B.M., Patel, K.D., Bohannon, A.S., Patel, A., Fox, S.N., Simmons, M.S., Day, J.J., Kralli, A., Crossman, D.K., Cowell, R.M.
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Sprache:eng
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Zusammenfassung:•ERR binding sites are enriched in the promoter region of PGC-1α-responsive genes.•ERRα antagonism impedes the ability of PGC-1α to upregulate genes in vitro.•ERRα and PGC-1α are colocalized in parvalbumin-expressing interneurons.•ERRα deletion leads to reductions in PGC-1α-dependent transcripts in vivo.•ERRα null mice exhibit schizophrenia-like behaviors. Deficiency in peroxisome proliferator-activated receptor gamma coactivator 1-alpha. (PGC-1α) expression or function is implicated in numerous neurological and psychiatric disorders. PGC-1α is required for the expression of genes involved in synchronous neurotransmitter release, axonal integrity, and metabolism, especially in parvalbumin-positive interneurons. As a transcriptional coactivator, PGC-1α requires transcription factors to specify cell-type-specific gene programs; while much is known about these factors in peripheral tissues, it is unclear if PGC-1α utilizes these same factors in neurons. Here, we identified putative transcription factors controlling PGC-1α-dependent gene expression in the brain using bioinformatics and then validated the role of the top candidate in a knockout mouse model. We transcriptionally profiled cells overexpressing PGC-1α and searched for over-represented binding motifs in the promoters of upregulated genes. Binding sites of the estrogen-related receptor (ERR) family of transcription factors were enriched, and blockade of ERRα attenuated PGC-1α-mediated induction of mitochondrial and synaptic genes in cell culture. Localization in the mouse brain revealed enrichment of ERRα expression in parvalbumin-expressing neurons with tight correlation of expression with PGC-1α across brain regions. In ERRα null mice, PGC-1α-dependent genes were reduced in multiple regions, including neocortex, hippocampus, and cerebellum, though not to the extent observed in PGC-1α null mice. Behavioral assessment revealed ambulatory hyperactivity in response to amphetamine and impairments in sensorimotor gating without the overt motor impairment characteristic of PGC-1α null mice. These data suggest that ERRα is required for normal levels of expression of PGC-1α-dependent genes in neurons but that additional factors may be involved in their regulation.
ISSN:0306-4522
1873-7544
DOI:10.1016/j.neuroscience.2021.10.007