HYPOTHALAMIC PREPROSOMATOSTATIN MESSENGER-RIBONUCLEIC-ACID EXPRESSIONIN MICE TRANSGENIC FOR EXCESS OR DEFICIENT ENDOGENOUS GROWTH-HORMONE

The influence of altered endogenous GH status on somatostatin (somatot ropin release-inhibiting hormone; SRIF) gene expression was studied in two transgenic mouse models. Transgenic dwarf mice carried the rat GH gene promoter fused to the diphtheria toxin A-chain gene, placing tox in expression under GH promoter control. As a result, the toxic produc t of the transgene ablated all GH-expressing cells, resulting in undet ectable circulating GH, reduced weight (10.6 +/- 1.0 g for transgenic dwarfs vs. 29.5 +/- 1.7 g for controls; P < 0.001), and no detectable somatotrophs. Transgenic giant mice contained a construction combining a widely expressed metallothionein promoter and the human GH-releasin g hormone (hGHRF) structural gene. Transgene expression of hGHRF resul ted in over-production of endogenous mouse GH in the anterior pituitar y and weight increases (42.7 +/- 2.7 g for giants vs. 29.5 +/- 1.7 g f or controls; P < 0.005). Using in situ hybridization, control mice, tr ansgenic dwarfs, and transgenic giants were compared for levels of pre pro-SRIF mRNA. Hybridization signal intensities for prepro-SRIF mRNA w ere similar in transgenic dwarfs to those in littermate nontransgenic mice in non-GH-regulating regions of the brain, such as cortex (contro l, 31 +/- 2 U; dwarf, 27 +/- 2) and reticulothalamic nucleus (control, 41 +/- 2 U; dwarfs, 39 +/- 3). Transgenic giant mice had hybridizatio n intensity of SRIF mRNA similar to that of normals in cortex (control s, 31 +/- 2 U; giant, 27 +/- 1) and reticulothalamic nucleus (controls , 41 +/- 2 U; giant, 40 +/- 4). In the GH-regulating neurons of the an terior periventricular hypothalamus (PeN), prepro-SRIF mRNA signal in transgenic dwarf mice decreased to 60% of that in controls (88 +/- 13 U for dwarfs vs. 147 +/- 17 U for controls; P < 0.01), although the nu mbers of mRNA-expressing cells in the PeN were not different between t he transgenic dwarfs and controls (dwarfs, 69 +/- 6 cells; controls, 7 2 +/- 4 cells). The transgenic giant mice had 230% higher prepro-SRIF mRNA signal than control mice in the PeN (343 +/- 30 U in giants vs. 1 47 +/- 17 U in controls; P < 0.001). Again, the numbers of mRNA-expres sing cells were not different in giants (57 +/- 9) and normals (72 +/- 4). These results suggest that while the lack of endogenous GH is acc ompanied by a slight decrease in transcriptional expression of SRIF in the PeN, the overproduction of endogenous GH greatly stimulates hypot halamic SRIF steady state mRNA levels.