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Submitted on January 30, 2004
Accepted on May 10, 2004
Division of Endocrinology, and The Ilyssa Center for Molecular and Cellular Endocrinology, The Johns Hopkins University School of Medicine, Baltimore MD 21287
* To whom correspondence should be addressed. E-mail: salvator{at}jhmi.edu.
The proliferation of pituitary somatotroph cells and the synthesis and secretion of GH are under the stimulatory control of the hypothalamic peptide GH-releasing hormone (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). While mutations in the GHRH receptor (GHRH-R) cause isolated GH deficiency (GHD) 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 (knock out, KO) 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% +/- and 21.4% -/-), showing no lethality in the GHRHKO embryos. GHRHKO mice appeared normal at birth. Starting at 3 weeks of age, -/- mice showed significant growth retardation. By 12 weeks of age, their weight was about 60% of +/+ and +/- littermates. Growth retardation was due to GH deficiency, as shown by reduced pituitary GH mRNA and protein content, reduced serum IGF-1, and reduced liver IGF-1 mRNA. The phenotype of the GHRHKO mice is similar to the one observed in the mouse with mutated GHRH-R, including pituitary hypoplasia. Heterozygous mice had normal growth, although adult +/- males (but not females) had mild reduction in serum IGF-1.
In conclusion, we demonstrate that ablation of the GHRH gene causes GHD in mice. The GHRHKO mouse will be new useful model of isolated GHD.
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