Department of Psychiatry, Université de Montréal, Montreal, Quebec, Canada.
Center for Advanced Research in Sleep Medicine and Research Center, Hôpital du Sacré-Cœur de Montréal, Montreal, Quebec, Canada.
J Biol Rhythms. 2018 Apr;33(2):166-178. doi: 10.1177/0748730418761236.
NEUROLIGIN-1 (NLGN1) is a postsynaptic adhesion molecule involved in the regulation of glutamatergic transmission. It has been associated with several features of sleep and psychiatric disorders. Our previous work suggested that transcription of the Nlgn1 gene could be regulated by the transcription factors CLOCK and BMAL1 because they bind to the Nlgn1 gene promoter in vivo. However, whether CLOCK/BMAL1 can directly activate Nlgn1 transcription is not yet known. We thus aimed to verify whether CLOCK/BMAL1, as well as their homologs NPAS2 and BMAL2, can activate transcription via the Nlgn1 promoter by using luciferase assays in COS-7 cells. We also investigated how Nlgn1 expression was affected in Clock mutant mice. Our results show transcriptional activation in vitro mediated by CLOCK/BMAL1 and by combinations with their homologs NPAS2 and BMAL2. Moreover, CLOCK/BMAL1 activation via the Nlgn1 gene fragment was repressed by GSK3β. In vivo, Nlgn1 mRNA expression was significantly modified in the forebrain of Clock mutant mice in a transcript variant-dependent manner. However, no significant change in NLGN1 protein level was observed in Clock mutant mice. These findings will increase knowledge about the transcriptional regulation of Nlgn1 and the relationship between circadian rhythms, mental health, and sleep.
神经黏连素 1（NLGN1）是一种突触后黏附分子，参与调节谷氨酸能传递。它与睡眠和精神障碍的几个特征有关。我们之前的工作表明，转录因子 CLOCK 和 BMAL1 可以调节 Nlgn1 基因的转录，因为它们在体内与 Nlgn1 基因启动子结合。然而，CLOCK/BMAL1 是否可以直接激活 Nlgn1 转录尚不清楚。因此，我们旨在通过 COS-7 细胞中的荧光素酶测定来验证 CLOCK/BMAL1 及其同源物 NPAS2 和 BMAL2 是否可以通过 Nlgn1 启动子直接激活转录。我们还研究了 Clock 突变小鼠中 Nlgn1 表达如何受到影响。我们的结果表明，CLOCK/BMAL1 及其同源物 NPAS2 和 BMAL2 可在体外介导转录激活。此外，GSK3β 抑制了 CLOCK/BMAL1 通过 Nlgn1 基因片段的激活。在体内，Clock 突变小鼠的前脑中 Nlgn1 mRNA 表达在转录变体依赖性方面发生了显著修饰。然而，在 Clock 突变小鼠中未观察到 NLGN1 蛋白水平的显著变化。这些发现将增加关于 Nlgn1 转录调控以及昼夜节律、心理健康和睡眠之间关系的知识。
