Grino M, Burgunder J M, Eskay R L, Eiden L E
Unit on Molecular and Cellular Neurobiology, Laboratory of Cell Biology, National Institute of Mental Health, Bethesda, Maryland 20892.
Endocrinology. 1989 Jun;124(6):2686-92. doi: 10.1210/endo-124-6-2686.
Expression of the CRF gene in the hypothalamus and that of the POMC gene in the anterior pituitary are reduced during the first week of life in the rat. During this so-called stress nonresponsive period (SNRP), stimuli such as ether vapors, electroshocks, and hypoxia do not elicit ACTH secretion from the pituitary, as occurs later in development. The current hypothesis to explain the SNRP is an increased negative glucocorticoid feedback on POMC and CRF synthesis and/or release during this time. To test this hypothesis we studied the effects of adrenalectomy (ADX) on anterior pituitary POMC mRNA expression. In 7-day-old rats POMC mRNA levels were increased only 3-fold 48 h post-ADX, compared to a 7-fold increase in 14-day-old animals. This blunted effect of endogenous glucocorticoid removal on pituitary POMC mRNA could be due to decreased up-regulation of CRF after removal of glucocorticoids or normal up-regulation of CRF but decreased pituitary responsiveness to CRF relative to those in 14-day-old animals. Therefore, we studied in vitro beta-endorphin release from pituitaries obtained from 7- and 14-day-old rats. CRF stimulated basal beta-endorphin release to the same extent in pituitaries from both groups. The inhibition by corticosterone of CRF-stimulated beta-endorphin secretion was also indistinguishable in pituitaries obtained from 7- or 14-day-old rats. Since the responsiveness of the 7-day-old pituitary was normal, the blunted enhancement of POMC biosynthesis after ADX must be mediated at the level of the hypothalamus. Indeed, in situ hybridization showed that while in 14-day-old rats ADX induced a significant increase [190 +/- 10% (+/- SE) of control; n = 5; P less than 0.0005] in hypothalamic mRNA levels, ADX did not change the expression of the CRF gene in the paraventricular nucleus of 7-day-old rats, indicating a lack of glucocorticoid modulation of hypothalamic CRF synthesis. Finally, we studied the effects of 48 h CRF treatment on the post-ADX increase in POMC mRNA levels in 7-day-old rats. Daily injections of 200 ng CRF/rat induced an increase in anterior pituitary POMC mRNA concentrations [669 +/- 139% (+/- SE) of control; n = 6; P less than 0.02 vs. adrenalectomized vehicle-treated rats] comparable to that in adrenalectomized untreated 14-day-old rats. In conclusion, our data indicate that the glucocorticoid regulation of hypothalamic CRF gene expression is not mature during the first week of life, i.e. within the so-called SNRP.(ABSTRACT TRUNCATED AT 400 WORDS)
在大鼠出生后的第一周，下丘脑促肾上腺皮质激素释放因子（CRF）基因的表达以及垂体前叶阿黑皮素原（POMC）基因的表达会降低。在这个所谓的应激无反应期（SNRP），诸如乙醚蒸汽、电击和低氧等刺激不会像在发育后期那样引起垂体促肾上腺皮质激素（ACTH）的分泌。目前用于解释SNRP的假说是，在此期间糖皮质激素对POMC和CRF合成及/或释放的负反馈增加。为了验证这一假说，我们研究了肾上腺切除术（ADX）对垂体前叶POMC mRNA表达的影响。与14日龄动物7倍的增加相比，7日龄大鼠在ADX后48小时POMC mRNA水平仅增加了3倍。内源性糖皮质激素去除对垂体POMC mRNA的这种钝化作用可能是由于去除糖皮质激素后CRF的上调减少，或者是CRF正常上调但相对于14日龄动物垂体对CRF的反应性降低。因此，我们研究了从7日龄和14日龄大鼠获得的垂体在体外β-内啡肽的释放情况。CRF对两组垂体基础β-内啡肽释放的刺激程度相同。从7日龄或14日龄大鼠获得的垂体中，皮质酮对CRF刺激的β-内啡肽分泌的抑制作用也没有差异。由于7日龄垂体的反应性正常，ADX后POMC生物合成的钝化增强一定是在下丘脑水平介导的。事实上，原位杂交显示，虽然在14日龄大鼠中ADX诱导下丘脑mRNA水平显著增加[相对于对照组增加190±10%（±标准误）；n = 5；P < 0.0005]，但ADX并没有改变7日龄大鼠室旁核中CRF基因的表达，这表明下丘脑CRF合成缺乏糖皮质激素调节。最后，我们研究了48小时CRF治疗对7日龄大鼠ADX后POMC mRNA水平升高的影响。每天注射200 ng CRF/大鼠可诱导垂体前叶POMC mRNA浓度增加[相对于对照组增加669±139%（±标准误）；n = 6；与肾上腺切除后给予赋形剂处理的大鼠相比，P < 0.02]，与未处理的肾上腺切除14日龄大鼠相当。总之，我们的数据表明，在出生后的第一周，即所谓的SNRP期间，下丘脑CRF基因表达的糖皮质激素调节尚未成熟。（摘要截短至400字）
