Johnston Jonathan D, Messager Sophie, Ebling Francis J P, Williams Lynda M, Barrett Perry, Hazlerigg David G
School of Biological Sciences, University of Aberdeen, Aberdeen AB24 5UA, United Kingdom.
Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2831-5. doi: 10.1073/pnas.0436184100. Epub 2003 Feb 21.
Melatonin is produced nocturnally by the pineal gland and is a neurochemical representation of time. It regulates neuroendocrine target tissues through G-protein-coupled receptors, of which MT(1) is the predominant subtype. These receptors are transiently expressed in several fetal and neonatal tissues, suggesting distinct roles for melatonin in development and that specific developmental cues define time windows for melatonin sensitivity. We have investigated MT(1) gene expression in the rat pituitary gland. MT(1) mRNA is confined to the pars tuberalis region of the adult pituitary, but in neonates extends into the ventral pars distalis and colocalizes with luteinizing hormone beta-subunit (LH beta) expression. This accounts for the well documented transient sensitivity of rat gonadotrophs to melatonin in the neonatal period. Analysis of an upstream fragment of the rat MT(1) gene revealed multiple putative response elements for the transcription factor pituitary homeobox-1 (Pitx-1), which is expressed in the anterior pituitary from Rathke's pouch formation. A Pitx-1 expression vector potently stimulated expression of both MT(1)-luciferase and LH beta-luciferase reporter constructs in COS-7 cells. Interestingly, transcription factors that synergize with Pitx-1 to trans-activate gonadotroph-associated genes did not potentiate Pitx-1-induced MT(1)-luciferase activity. Moreover, the transcription factor, early growth response factor-1, which is induced by gonadotrophin-releasing hormone (GnRH) and trans-activates LH beta expression, attenuated Pitx-1-induced MT(1)-luciferase activity. Finally, pituitary MT(1) gene expression was 4-fold higher in hypogonadal (hpg) mice, which do not synthesize GnRH, than in their wild-type littermates. These data suggest that establishment of a mature hypothalamic GnRH input drives the postnatal decline in pituitary MT(1) gene expression.
褪黑素由松果体在夜间分泌，是时间的一种神经化学表征。它通过G蛋白偶联受体调节神经内分泌靶组织，其中MT(1)是主要亚型。这些受体在几种胎儿和新生儿组织中短暂表达，提示褪黑素在发育过程中具有独特作用，且特定的发育线索决定了褪黑素敏感性的时间窗口。我们研究了大鼠垂体中MT(1)基因的表达。MT(1) mRNA局限于成年垂体的结节部区域，但在新生儿中延伸至远侧部腹侧，并与促黄体生成素β亚基（LHβ）表达共定位。这解释了大鼠促性腺细胞在新生儿期对褪黑素具有充分记录的短暂敏感性。对大鼠MT(1)基因上游片段的分析揭示了转录因子垂体同源框-1（Pitx-1）的多个假定反应元件，Pitx-1从拉特克囊形成时就在垂体前叶表达。一个Pitx-1表达载体在COS-7细胞中强烈刺激MT(1)-荧光素酶和LHβ-荧光素酶报告构建体的表达。有趣的是，与Pitx-1协同反式激活促性腺细胞相关基因的转录因子并不能增强Pitx-1诱导的MT(1)-荧光素酶活性。此外，由促性腺激素释放激素（GnRH）诱导并反式激活LHβ表达的转录因子早期生长反应因子-1减弱了Pitx-1诱导的MT(1)-荧光素酶活性。最后，在不合成GnRH的性腺功能减退（hpg）小鼠中，垂体MT(1)基因表达比其野生型同窝小鼠高4倍。这些数据表明，成熟的下丘脑GnRH输入的建立驱动了垂体MT(1)基因表达在出生后的下降。
