Npas4 is activated by melatonin, and drives the clock gene Cry1 in the ovine pars tuberalis.
Npas4 is activated by melatonin, and drives the clock gene Cry1 in the ovine pars tuberalis.
复制标题
NPAS4被褪黑激素激活，并驱动卵形pars tuberalis中的时钟基因Cry1。
DOI：
10.1210/me.2012-1366
复制
发表时间：
2013-06
期刊：
影响因子：
--
通讯作者：
Loudon AS
中科院分区：
文献类型：
--
作者：
West A;Dupré SM;Yu L;Paton IR;Miedzinska K;McNeilly AS;Davis JR;Burt DW;Loudon AS
季节性哺乳动物整合夜间褪黑激素分泌持续时间的变化，以驱动年度生理周期。褪黑激素受体在近端垂体区域，结节部（PT），是必不可少的调节季节性神经内分泌反应。在绵羊PT中，已知褪黑激素影响转录动力学的急性变化，其与褪黑激素分泌的开始（黄昏）和偏移（黎明）相耦合，从而导致能够解码日长（光周期）变化的潜在间隔定时机制。褪黑激素在黎明时的偏移与cAMP积累有关，cAMP积累直接诱导时钟基因Per 1的转录。黄昏时褪黑激素的增加诱导了一个独立而独特的群体，包括时钟调节基因Cry 1和Nampt，但对所涉及的上游机制知之甚少。在这里，我们使用下一代测序的绵羊PT转录组在褪黑激素的发病和确定Npas 4作为一个快速诱导的碱性螺旋-环-螺旋Per-Arnt-Sim结构域转录因子。在体内，我们显示NPAS 4蛋白在PT的假定褪黑激素靶细胞（α-糖蛋白酶表达细胞）中的核定位，而原位杂交研究确定了NPAS 4对褪黑激素的反应在PT中的急性和瞬时表达。在体外，NPAS 4与碱性螺旋环螺旋-PAS结构域辅因子芳烃受体核转运子（ARNT）、ARNT 2和ARNTL形成功能性二聚体，反式激活Cry 1和Nampt绵羊启动子报告基因。使用5′-缺失和定点突变的组合，我们显示NPAS 4-ARNT反式激活共依赖于Cry 1启动子内的两个保守的中央中线元件。因此，我们的数据揭示NPAS 4作为候选人立即早期反应基因在绵羊PT，驱动分子反应褪黑激素。
Seasonal mammals integrate changes in the duration of nocturnal melatonin secretion to drive annual physiologic cycles. Melatonin receptors within the proximal pituitary region, the pars tuberalis (PT), are essential in regulating seasonal neuroendocrine responses. In the ovine PT, melatonin is known to influence acute changes in transcriptional dynamics coupled to the onset (dusk) and offset (dawn) of melatonin secretion, leading to a potential interval-timing mechanism capable of decoding changes in day length (photoperiod). Melatonin offset at dawn is linked to cAMP accumulation, which directly induces transcription of the clock gene Per1. The rise of melatonin at dusk induces a separate and distinct cohort, including the clock-regulated genes Cry1 and Nampt, but little is known of the up-stream mechanisms involved. Here, we used next-generation sequencing of the ovine PT transcriptome at melatonin onset and identified Npas4 as a rapidly induced basic helix-loop-helix Per-Arnt-Sim domain transcription factor. In vivo we show nuclear localization of NPAS4 protein in presumptive melatonin target cells of the PT (α-glycoprotein hormone-expressing cells), whereas in situ hybridization studies identified acute and transient expression in the PT of Npas4 in response to melatonin. In vitro, NPAS4 forms functional dimers with basic helix loop helix-PAS domain cofactors aryl hydrocarbon receptor nuclear translocator (ARNT), ARNT2, and ARNTL, transactivating both Cry1 and Nampt ovine promoter reporters. Using a combination of 5′-deletions and site-directed mutagenesis, we show NPAS4-ARNT transactivation to be codependent upon two conserved central midline elements within the Cry1 promoter. Our data thus reveal NPAS4 as a candidate immediate early-response gene in the ovine PT, driving molecular responses to melatonin.
登录
查看更多内容
影响因子：
64.8
作者：
Lin, Yingxi;Bloodgood, Brenda L.;Hauser, Jessica L.;Lapan, Ariya D.;Koon, Alex C.;Kim, Tae-Kyung;Hu, Linda S.;Malik, Athar N.;Greenberg, Michael E.
通讯作者：
Greenberg, Michael E.
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
DOI：
10.1016/s0169-328x(03)00134-7
发表时间：
2003-06-10
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Dardente, H;Menet, JS;Masson-Pévet, M
通讯作者：
Masson-Pévet, M
影响因子：
4.8
作者：
Lincoln, GA;Johnston, JD;Hazlerigg, DG
通讯作者：
Hazlerigg, DG
影响因子：
4.8
作者：
Dupre, Sandrine M.;Burt, Dave W.;Loudon, Andrew S. I.
通讯作者：
Loudon, Andrew S. I.