Consiglio Nazionale delle Ricerche (CNR) Institute of Neuroscience, Department of Pharmacology, University of Milan, Milan, Italy.
Nat Neurosci. 2011 Aug 28;14(10):1293-301. doi: 10.1038/nn.2911.
Oligophrenin-1 regulates dendritic spine morphology in the brain. Mutations in the oligophrenin-1 gene (OPHN1) cause intellectual disability. We discovered a previously unknown partner of oligophrenin-1, Rev-erbα, a nuclear receptor that represses the transcription of circadian oscillators. We found that oligophrenin-1 interacts with Rev-erbα in the mouse brain, causing it to locate to dendrites, reducing its repressor activity and protecting it from degradation. Our results indicate the presence of a circadian oscillator in the hippocampus, involving the clock gene Bmal1 (also known as Arntl), that is modulated by Rev-erbα and requires oligophrenin-1 for normal oscillation. We also found that synaptic activity induced Rev-erbα localization to dendrites and spines, a process that is mediated by AMPA receptor activation and requires oligophrenin-1. Our data reveal new interactions between synaptic activity and circadian oscillators, and delineate a new means of communication between nucleus and synapse that may provide insight into normal plasticity and the etiology of intellectual disability.
寡啡肽-1 调节大脑中的树突棘形态。寡啡肽-1 基因 (OPHN1) 的突变导致智力障碍。我们发现了寡啡肽-1 的一个先前未知的伙伴，即核受体 Rev-erbα，它抑制生物钟振荡器的转录。我们发现寡啡肽-1 在小鼠大脑中与 Rev-erbα相互作用，导致其定位到树突上，降低其抑制活性并防止其降解。我们的结果表明，海马体中存在一个生物钟振荡器，涉及时钟基因 Bmal1（也称为 Arntl），该振荡器受 Rev-erbα调节，并且需要寡啡肽-1 才能正常振荡。我们还发现，突触活动诱导 Rev-erbα定位到树突和棘上，这一过程是由 AMPA 受体激活介导的，需要寡啡肽-1。我们的数据揭示了突触活动和生物钟振荡器之间的新相互作用，并描绘了核和突触之间新的通讯方式，这可能为正常的可塑性和智力障碍的病因提供了新的见解。
