Reed D K, Korytko A I, Hipkin R W, Wehrenberg W B, Schonbrunn A, Cuttler L
Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Endocrinology. 1999 Oct;140(10):4739-44. doi: 10.1210/endo.140.10.7033.
The capacity of the pituitary to suppress hormone secretion in response to somatostatin (SRIF) is markedly age dependent. Immature pituitaries are relatively resistant to SRIF effects, and increasing sensitivity to SRIF with advancing age is believed to cause characteristic developmental changes in pituitary hormone secretion in mammals. However, the cellular mechanism(s) underlying this developmental pattern of response to SRIF are not understood. Because somatostatin receptors (ssts) are critical mediators of SRIF's actions on target tissues, we investigated the expression of sst1, sst2, sst3, sst4, and sst5 messenger RNA (mRNA) in pituitaries of developing and mature rats. Animals were studied at embryonic day 19.5, and at postnatal days 2, 12, 30, 45, 70, and 1 yr; these ages correspond to major changes in circulating GH levels and pituitary responsiveness to SRIF. Pituitary levels of sst2 mRNA increased strikingly and progressively with advancing age after birth (F = 30.92, P < 0.0001). Compared with 2-day-old pituitaries, sst2 mRNA abundance rose 3.25-fold by 12 days of age and 6-fold by 70 days of age. Moreover, Western blot analysis indicated a marked increase in pituitary expression of sst2A protein with advancing age. By contrast, pituitary abundance of sst1, sst3, sst4, and sst5 mRNAs did not differ with age. To assess the role of endogenous SRIF in regulating perinatal sst2 gene expression, we also administered a well-characterized SRIF antiserum (or NSS as controls; 10 microl/10 g) sc daily from postnatal days 2 to 12 of life. Treatment with SRIF antiserum raised GH levels but did not alter pituitary sst2 mRNA abundance, compared with controls. Taken together, these data indicate that 1) the perinatal rat pituitary expresses the same complement of ssts as the adult pituitary; 2) expression of ssts is developmentally regulated in a highly subtype-specific manner; 3) pituitary sst2 mRNA and sst2A protein increase markedly and progressively with advancing age after birth; and 4) the perinatal rise in sst2 mRNA levels is unlikely to be regulated by endogenous SRIF. The finding of subtype-specific, developmentally determined sst expression indicates a novel and potentially fundamental mechanism of sst regulation, and suggests a molecular mechanism underlying developmental maturation in the capacity of the pituitary to respond to SRIF.
垂体对生长抑素（SRIF）作出反应以抑制激素分泌的能力明显依赖于年龄。未成熟的垂体对SRIF的作用相对不敏感，随着年龄的增长对SRIF的敏感性增加被认为会导致哺乳动物垂体激素分泌出现特征性的发育变化。然而，这种对SRIF反应的发育模式背后的细胞机制尚不清楚。由于生长抑素受体（ssts）是SRIF对靶组织作用的关键介质，我们研究了发育中和成熟大鼠垂体中sst1、sst2、sst3、sst4和sst5信使核糖核酸（mRNA）的表达。在胚胎第19.5天以及出生后第2、12、30、45、70天和1岁时对动物进行研究；这些年龄对应于循环生长激素水平和垂体对SRIF反应性的主要变化。出生后垂体中sst2 mRNA水平随着年龄的增长显著且逐渐升高（F = 30.92，P < 0.0001）。与2日龄的垂体相比，sst2 mRNA丰度在12日龄时增加了3.25倍，在70日龄时增加了6倍。此外，蛋白质印迹分析表明随着年龄的增长垂体中sst2A蛋白的表达显著增加。相比之下，垂体中sst1、sst3、sst4和sst5 mRNA的丰度在不同年龄没有差异。为了评估内源性SRIF在调节围产期sst2基因表达中的作用，我们还在出生后第2天至12天每天皮下注射一种特征明确的SRIF抗血清（或作为对照的生理盐水；10微升/10克）。与对照组相比，用SRIF抗血清治疗可提高生长激素水平，但不会改变垂体sst2 mRNA的丰度。综上所述，这些数据表明：1）围产期大鼠垂体表达与成年垂体相同的ssts；2）ssts的表达以高度亚型特异性的方式受到发育调节；3）出生后垂体sst2 mRNA和sst2A蛋白随着年龄的增长显著且逐渐增加；4）围产期sst2 mRNA水平的升高不太可能受内源性SRIF调节。亚型特异性、发育决定的sst表达的发现表明了一种新的且可能是基本的sst调节机制，并提示了垂体对SRIF反应能力发育成熟的分子机制。
