Estrogen-related Receptor Alpha (ERRα) is Required for PGC-1α-dependent Gene Expression in the Mouse Brain. (15th December 2021)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Neuroscience. Volume 479(2021)
• Page Start: 70
• Page End: 90
• Publication Date: 2021-12-15
• Subjects: PGC-1α -- ERRα -- transcription -- parvalbumin -- interneurons; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2021.10.007
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: 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. Abstract: 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.