Szabo M, Butz M R, Banerjee S A, Chikaraishi D M, Frohman L A
Department of Medicine, University of Illinois at Chicago 60612, USA.
Endocrinology. 1995 Sep;136(9):4044-8. doi: 10.1210/endo.136.9.7649113.
Transgenic mice expressing a tyrosine hydroxylase-human (h) GH fusion gene in the hypothalamus exhibit a dwarf phenotype. The GH feedback mechanism(s) underlying the growth retardation in these animals was investigated by assessing peptide and messenger RNA (mRNA) levels of the hormones of the hypothalamic-GH-IGF-I axis. Pituitary GH content, hypothalamic GH-releasing hormone (GHRH) and somatostatin (SRIH) content, and serum IGF-I levels were measured by RIA. mRNA levels of hypothalamic GHRH and SRIH and of pituitary GH and the GHRH receptor were measured by Northern blot hybridization. Transgenic mice of both sexes and their wild-type littermates were studied at 2-4 months of age. The pituitary GH content was markedly reduced by 85% in male and by 87% in female transgenic mice compared to that in wild-type controls (P < 0.01 for both). The pituitary GH mRNA content was also decreased by 73% (P = 0.002) in transgenic male mice. Circulating IGF-I levels were significantly reduced by 66% and 68% in male and female transgenic mice, respectively (P = 0.001). The hypothalamic GHRH content was significantly reduced by 19% and 33% (P < 0.05) in male and female transgenic mice, respectively. No significant difference was detected, however, in the hypothalamic SRIH content between wild-type and transgenic mice. Hypothalamic GHRH mRNA levels were significantly decreased by 35% (P = 0.002) in transgenic male mice compared to those in wild-type littermates. In contrast, SRIH mRNA was not significantly changed. An even greater reduction (61%; P = 0.003) was observed in pituitary GHRH receptor mRNA in transgenic mice. These data indicate that the GH deficiency and dwarf phenotype of the tyrosine hydroxylase-hGH transgenic mouse can be attributed primarily to impaired hypothalamic GHRH production. The mechanism of GH feedback inhibition appears to involve direct suppression of GHRH gene expression by locally produced hGH in the hypothalamus.
在下丘脑表达酪氨酸羟化酶-人（h）生长激素融合基因的转基因小鼠表现出侏儒表型。通过评估下丘脑-生长激素-胰岛素样生长因子-I轴激素的肽和信使核糖核酸（mRNA）水平，研究了这些动物生长迟缓背后的生长激素反馈机制。用放射免疫分析法测定垂体生长激素含量、下丘脑生长激素释放激素（GHRH）和生长抑素（SRIH）含量以及血清胰岛素样生长因子-I水平。用Northern印迹杂交法测定下丘脑GHRH和SRIH以及垂体生长激素和GHRH受体的mRNA水平。对2至4月龄的雌雄转基因小鼠及其野生型同窝仔鼠进行了研究。与野生型对照相比，雄性转基因小鼠的垂体生长激素含量显著降低了85%，雌性降低了87%（两者P均<0.01）。转基因雄性小鼠的垂体生长激素mRNA含量也降低了73%（P = 0.002）。雄性和雌性转基因小鼠的循环胰岛素样生长因子-I水平分别显著降低了66%和68%（P = 0.001）。雄性和雌性转基因小鼠的下丘脑GHRH含量分别显著降低了19%和33%（P < 0.05）。然而，野生型和转基因小鼠的下丘脑SRIH含量未检测到显著差异。与野生型同窝仔鼠相比，转基因雄性小鼠的下丘脑GHRH mRNA水平显著降低了35%（P = 0.002）。相比之下，SRIH mRNA没有显著变化。转基因小鼠垂体GHRH受体mRNA的降低更为明显（61%；P = 0.003）。这些数据表明，酪氨酸羟化酶-hGH转基因小鼠的生长激素缺乏和侏儒表型主要可归因于下丘脑GHRH产生受损。生长激素反馈抑制机制似乎涉及下丘脑局部产生的hGH对GHRH基因表达的直接抑制。
