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Development of a Transgenic Mouse That Overexpresses a Novel Product of the Growth Hormone-Releasing Hormone Gene¹

Section of Pediatric Endocrinology/Diabetology, Wells Center for Pediatric Research, Department of Pediatrics (S.F., R.S., D.W.K., P.Z., O.H.P.); Laboratory Animal Resource Center, Indiana University School of Medicine (C.V.); and Department of Microbiology and Immunology and The Walther Cancer Institute (S.C., G.H., H.E.B.), Indiana University School of Medicine, Indianapolis, Indiana 46202

Address all correspondence and requests for reprints to: Dr. Ora H. Pescovitz, Riley Hospital, Room A5984, 702 Barnhill Drive, Indianapolis, Indiana 46202. E-mail: opescovi{at}iupui.edu

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 kinase gene, selectively expresses GHRH-RP, but not GHRH. Western blot analysis confirmed that the transgene produces GHRH-RP. Animals were evaluated for the effect of excess GHRH-RP on growth, fertility, behavior, stem cell factor (SCF) expression, and hematopoiesis. Northern blot and RT-PCR were used to demonstrate ubiquitous expression of the transgene in tissues from GHRH-RP Tg animals. These tissues also had marked overexpression of SCF messenger RNA compared with controls. Tg animals had significantly increased cell cycling for granulocyte-macrophage, erythroid, and multilineage progenitor cells. Transgenic animals did not differ from control mice in their growth, fertility, 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 hematopoiesis in vivo and suggests that GHRH-RP may play a role in normal blood cell development.

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