Johnston J D, Klosen P, Barrett P, Hazlerigg D G
School of Biological Sciences, University of Aberdeen, Tinnydrone Avenue, Aberdeen B24 2TZ, Scotland, UK.
J Neuroendocrinol. 2006 Jan;18(1):50-6. doi: 10.1111/j.1365-2826.2005.01389.x.
During development, melatonin receptors are transiently expressed in multiple neuroendocrine tissues, suggesting a novel role for melatonin in developmental physiology. The best characterised model of melatonin signalling during development is the pars distalis of the rat pituitary. However, although many studies have characterised the postnatal decline of melatonin receptors in the rat pars distalis, the mechanism(s) that time the developmental onset of receptor expression during embryogenesis are unknown. Analysis of these mechanisms may yield important information regarding the putative role of melatonin in neuroendocrine development. Here, we report the expression of MT(1) melatonin receptor mRNA in the rat pituitary from embryonic day 15.5 (e15.5). Prior to e15.5, the homeodomain transcription factor Msx-1, an inhibitor of cellular differentiation, is widely expressed throughout the pituitary. In transient transfection experiments, Msx-1 potently inhibited pituitary homeobox-1 (Pitx-1)-induced MT(1) promoter activity and therefore may represent a key inhibitor of MT(1) expression in early pituitary development. During late embryogenesis, MT(1) mRNA was expressed in both the ventral and dorsal pituitary. Analysis of a 1.5-kb fragment of the rat MT(1) promoter revealed four putative cis-elements for the POU domain factor Pit-1, which is associated with mid-dorsal cell lineages. Although Pit-1 induced a strong, dose-dependent stimulation of MT(1) promoter activity in vitro, dual-labelled in situ hybridisation revealed no colocalisation of MT(1) and Pit-1 mRNAs in vivo at e19.5. By contrast, all MT(1) positive cells colocalised with alphaGSU and most with betaTSH mRNA. Our data therefore implicate the decline of Msx-1 expression as a key event that times the onset of melatonin receptor expression to the differentiation of endocrine cells types in the developing pituitary gland, and suggest that the melatonin-sensitive cells in the embryonic pituitary are primarily Pit-1-independent thyrotrophs in the rostral pituitary, with a secondary population of pars distalis gonadotrophs.
在发育过程中，褪黑素受体在多种神经内分泌组织中短暂表达，这表明褪黑素在发育生理学中具有新的作用。发育过程中褪黑素信号传导的最佳特征模型是大鼠垂体的远侧部。然而，尽管许多研究已经描述了大鼠垂体远侧部中褪黑素受体的出生后下降情况，但在胚胎发生过程中确定受体表达发育起始时间的机制尚不清楚。对这些机制的分析可能会产生有关褪黑素在神经内分泌发育中假定作用的重要信息。在此，我们报告了大鼠垂体从胚胎第15.5天（e15.5）开始表达MT(1)褪黑素受体mRNA。在e15.5之前，同源结构域转录因子Msx-1（一种细胞分化抑制剂）在整个垂体中广泛表达。在瞬时转染实验中，Msx-1强烈抑制垂体同源框-1（Pitx-1）诱导的MT(1)启动子活性，因此可能代表早期垂体发育中MT(1)表达的关键抑制剂。在胚胎后期，MT(1) mRNA在垂体腹侧和背侧均有表达。对大鼠MT(1)启动子1.5 kb片段的分析揭示了与POU结构域因子Pit-1相关的四个假定顺式元件，Pit-1与中背侧细胞谱系有关。尽管Pit-1在体外诱导了强烈的、剂量依赖性的MT(1)启动子活性刺激，但双标记原位杂交显示在e19.5时体内MT(1)和Pit-1 mRNA没有共定位。相比之下，所有MT(1)阳性细胞都与αGSU共定位，并且大多数与βTSH mRNA共定位。因此，我们的数据表明Msx-1表达的下降是一个关键事件，它将褪黑素受体表达的起始时间与发育中垂体腺内分泌细胞类型的分化联系起来，并表明胚胎垂体中的褪黑素敏感细胞主要是垂体前部不依赖Pit-1的促甲状腺细胞，其次是远侧部促性腺细胞群体。
