AUTOFEEDBACK SUPPRESSION OF GROWTH-HORMONE (GH) SECRETION IN TRANSGENIC MICE EXPRESSING A HUMAN GH REPORTER TARGETED BY TYROSINE-HYDROXYLASE 5'-FLANKING SEQUENCES TO THE HYPOTHALAMUS

Transgenic mice expressing a tyrosine hydroxylase-human (h) GH fusion gene in the hypothalamus exhibit a dwarf phenotype. The GH feedback me chanism(s) underlying the growth retardation in these animals was inve stigated by assessing peptide and messenger RNA (mRNA) levels of the h ormones of the hypothalamic-GH-IGF-I axis. Pituitary GH content, hypot halamic GH-releasing hormone (GHRH) and somatostatin (SRIH) content, a nd serum IGF-I levels were measured by RIA. mRNA levels of hypothalami c GHRH and SRIH and of pituitary GH and the GHRH receptor were measure d by Northern blot hybridization. Transgenic mice of both sexes and th eir wild-type littermates were studied at 2-4 months of age. The pitui tary GH content was markedly reduced by 85% in male and by 87% in fema le transgenic mice compared to that in wild-type controls (P < 0.01 fo r both). The pituitary GH mRNA content was also decreased by 73% (P = 0.002) in transgenic male mice. Circulating IGF-I levels were signific antly reduced by 66% and 68% in male and female transgenic mice, respe ctively (P = 0.001). The hypothalamic GHRH content was significantly r educed by 19% and 33% (P < 0.05) in male and female transgenic mice, r espectively. No significant difference was detected, however, in the h ypothalamic SRIH content between wild-type and transgenic mice. Hypoth alamic GHRH mRNA. levels were significantly decreased by 35% (P = 0.00 2) 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 mR NA in transgenic mice. These data indicate that the GH deficiency and dwarf phenotype of the tyrosine hydroxylase-hGH transgenic mouse can b e attributed primarily to impaired hypothalamic GHRH production. The m echanism of GH feedback inhibition appears to involve direct suppressi on of GHRH gene expression by locally produced hGH in the hypothalamus .