| Title: | A mouse with targeted ablation of the growth hormone-releasing hormone gene: a new model of isolated growth hormone deficiency |
| Address: | "Division of Endocrinology, Johns Hopkins University School of Medicine, 1830 East Monument Street #333, Baltimore, Maryland 21287, USA" |
| ISSN/ISBN: | 0013-7227 (Print) 0013-7227 (Linking) |
| Abstract: | "The proliferation of pituitary somatotroph cells and the synthesis and secretion of GH are under the stimulatory control of the hypothalamic peptide GHRH. GHRH is initially synthesized as pre-prohormone and then enzymatically cleaved to its mature form (44 amino acids in humans and 42 in mice). Although mutations in the GHRH receptor cause isolated GH deficiency (IGHD) both in humans and mice, mutations in the GHRH gene have never been described. To determine the consequences of generalized lack of GHRH, we have created a mouse with targeted disruption (knockout) of the GHRH gene (GHRHKO). We have substituted a portion of the gene that encodes for the initial 14 amino acids of the 1-42 GHRH with a neomycin resistance cassette. Heterozygous founder (+/-) mice were mated to obtain -/- animals. The expected Mendelian ratio was conserved (25.8% of offspring were +/+, 52.8% were +/-, and 21.4% were -/-), showing no lethality in the GHRHKO embryos. GHRHKO mice appeared normal at birth. Starting at 3 wk of age, -/- mice showed significant growth retardation. By 12 wk of age, their weight was about 60% of +/+ and +/- littermates. Growth retardation was due to IGHD, as shown by reduced pituitary GH mRNA and protein content, reduced serum IGF-I, and reduced liver IGF-I mRNA. The phenotype of the GHRHKO mice is similar to the one observed in the mouse with mutated GHRH receptor, including pituitary hypoplasia. Heterozygous mice had normal growth, although adult +/- males (but not females) had mild reduction in serum IGF-I. In conclusion, we demonstrate that ablation of the GHRH gene causes IGHD in mice. The GHRHKO mouse will be the new useful model of IGHD" |
| Keywords: | "Animals *Disease Models, Animal Fertility Growth Hormone/*deficiency/metabolism Growth Hormone-Releasing Hormone/*genetics Hypothalamus/metabolism Insulin-Like Growth Factor I/genetics/metabolism Liver/physiology Mice *Mice, Knockout Pituitary Gland/metab;" |
| Notes: | "MedlineAlba, Maria Salvatori, Roberto eng R03 HD042465-01/HD/NICHD NIH HHS/ R03 HD046641-01/HD/NICHD NIH HHS/ Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. 2004/05/25 Endocrinology. 2004 Sep; 145(9):4134-43. doi: 10.1210/en.2004-0119. Epub 2004 May 20" |
