Development of a transgenic mouse that overexpresses a novel product of the growth hormone-releasing hormone gene

The GH-releasing hormone (GHRH) precursor molecule contains a 30-amino acid C-terminal region that has been designated GHRH-related peptide (GHRH-RP). To begin to understand the physiological role of GHRH-RP, transgenic (Tg) mice that constituitively express this peptide were developed. To generate these mice, a transgene (SS-RP) was constructed by overlap primer extension PCR. This transgene, under the control of the mouse phosphoglycerate kinas e gene, selectively expresses GHRH-RP, but not GHRH. Western blot analysis confirmed that the transgene produces GHRH-RP. Animals were evaluated for t he effect of excess GHRH-RP on growth, fertility, behavior, stem cell facto r (SCF) expression, and hematopoiesis. Northern blot and RT-PCR were used t o demonstrate ubiquitous expression of the transgene in tissues from GHRH-R P Tg animals. These tissues also had marked overexpression of SCF messenger RNA compared with controls. Tg animals had significantly increased cell cy cling for granulocyte-macrophage, erythroid, and multilineage progenitor ce lls. Transgenic animals did not differ from control mice in their growth, f ertility, or behavior. These findings demonstrate, for the first time, that in vivo the C-terminal peptide of the pro-GHRH molecule is a biologically active peptide that is capable of stimulating the expression of SCF and hem atopoiesis in vivo and suggests that GHRH-RP may play a role in normal bloo d cell development.