Estrogen-related Receptor Alpha (ERRα) is Required for PGC-1α-dependent Gene Expression in the Mouse Brain.
Estrogen-related Receptor Alpha (ERRα) is Required for PGC-1α-dependent Gene Expression in the Mouse Brain.
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雌激素相关受体α (ERRα)是小鼠大脑中pgc -1α依赖基因表达所必需的。
DOI：
10.1016/j.neuroscience.2021.10.007
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发表时间：
2021-12-15
期刊：
影响因子：
3.3
通讯作者：
Cowell, R. M.
中科院分区：
文献类型：
--
作者：
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.
过氧化物酶体增殖物激活受体γ辅活化子1-α(PGC-1α)的表达或功能缺陷与许多神经和精神疾病有关。PGC-1α是参与神经递质同步释放、轴突完整性和代谢的基因表达所必需的，尤其是在小白蛋白阳性的中间神经元中。作为一种转录辅助激活因子，pGC-1α需要转录因子来指定特定细胞类型的基因程序；虽然在外周组织中对这些因子了解很多，但尚不清楚pGC-1α是否在神经元中利用这些相同的因子。在这里，我们利用生物信息学确定了可能的转录因子，这些转录因子控制着pGC-1α依赖的基因在大脑中的表达，然后在小鼠基因敲除模型中验证了首选候选因子的作用。我们在转录水平上分析了过度表达pgc-1α的细胞，并在上调基因的启动子中寻找过度表达的结合基序。雌激素相关受体(ERR)家族转录因子的结合部位被丰富，阻断ERRα可减弱pGC-1α介导的线粒体和突触基因在细胞培养中的诱导。在小鼠脑内的定位显示，ERRα在表达小白蛋白的神经元中表达丰富，并且在不同脑区的表达与PGC-1α密切相关。在ERRα缺失的小鼠中，pGC-1α依赖的基因在多个区域减少，包括大脑皮层、海马体和小脑，但没有在pGC-1α缺失的小鼠观察到的程度。行为学评估显示，对苯丙胺的反应出现了动态多动，感觉运动门控受损，没有pGC-1α缺失小鼠的明显运动障碍特征。这些数据表明，ERRα是正常水平的pGC-1α依赖基因在神经元中表达所必需的，但其他因素可能参与了它们的调节。
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.
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影响因子：
3.5
作者：
Dempster EL;Pidsley R;Schalkwyk LC;Owens S;Georgiades A;Kane F;Kalidindi S;Picchioni M;Kravariti E;Toulopoulou T;Murray RM;Mill J
通讯作者：
Mill J
影响因子：
4.7
作者：
Brady, Lillian J.;Bartley, Aundrea F.;Dobrunz, Lynn E.
通讯作者：
Dobrunz, Lynn E.
影响因子：
48
作者：
Habib N;Avraham-Davidi I;Basu A;Burks T;Shekhar K;Hofree M;Choudhury SR;Aguet F;Gelfand E;Ardlie K;Weitz DA;Rozenblatt-Rosen O;Zhang F;Regev A
通讯作者：
Regev A
影响因子：
15.9
作者：
Cui, Huxing;Moore, Jarrette;Lutter, Michael
通讯作者：
Lutter, Michael
影响因子：
3.8
作者：
Holschneider, DP;Chen, K;Shih, JC
通讯作者：
Shih, JC