title: Transgenic expression of the human growth hormone minigene promotes pancreatic β-cell proliferation.
abstract: Transgenic mouse models are designed to study the role of specific proteins. To increase transgene expression the human growth hormone (hGH) minigene, including introns, has been included in many transgenic constructs. Until recently, it was thought that the hGH gene was not spliced, transcribed, and translated to produce functional hGH protein. We generated a transgenic mouse with the transcription factor Forkhead box M1 (FoxM1) followed by the hGH minigene, under control of the mouse insulin promoter (MIP) to target expression specifically in the pancreatic β-cell. Expression of FoxM1 in isolated pancreatic islets in vitro stimulates β-cell proliferation. We aimed to investigate the effect of FoxM1 on β-cell mass in a mouse model for diabetes mellitus. However, we found inadvertent coexpression of hGH protein from a spliced, bicistronic mRNA. MIP-FoxM1-hGH mice had lower blood glucose and higher pancreatic insulin content, due to increased β-cell proliferation. hGH signals through the murine prolactin receptor, and expression of its downstream targets tryptophan hydroxylase-1 (Tph1), tryptophan hydroxylase-2 (Tph2), and cytokine-inducible SH2 containing protein (Cish) was increased. Conversely, transcriptional targets of FoxM1 were not upregulated. Our data suggest that the phenotype of MIP-FoxM1-hGH mice is due primarily to hGH activity and that the FoxM1 protein remains largely inactive. Over the past decades, multiple transgenic mouse strains were generated that make use of the hGH minigene to increase transgene expression. Our work suggests that each will need to be carefully screened for inadvertent hGH production and critically evaluated for the use of proper controls.
authors.affiliation: Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison, Madison, Wisconsin; and.
authors.forename: Mieke
authors.initials: M
authors.lastname: Baan
authors.affiliation: Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison, Madison, Wisconsin; and.
authors.forename: Carly R
authors.initials: CR
authors.lastname: Kibbe
authors.affiliation: Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison, Madison, Wisconsin; and.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Bushkofsky
authors.affiliation: Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison, Madison, Wisconsin; and.
authors.forename: Ted W
authors.initials: TW
authors.lastname: Harris
authors.affiliation: Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison, Madison, Wisconsin; and.
authors.forename: Dawn S
authors.initials: DS
authors.lastname: Sherman
authors.affiliation: Department of Medicine, Division of Endocrinology, University of Wisconsin-Madison, Madison, Wisconsin; and William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin dbd@medicine.wisc.edu.
authors.forename: Dawn Belt
authors.identifier: http://orcid.org/0000-0002-0239-4715
authors.initials: DB
authors.lastname: Davis
mesh_terms: D000818:Animals; D000963:Antimetabolites; D001786:Blood Glucose / Q000378:metabolism; D001973:Bromodeoxyuridine; D049109:Cell Proliferation; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics; D005947:Glucose / Q000494:pharmacology; D051273:Glucose Transporter Type 2 / Q000096:biosynthesis / Q000235:genetics; D019382:Human Growth Hormone / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D019076:Transgenes / Q000235:genetics*
chemical_list: D000963:Antimetabolites; D001786:Blood Glucose; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D051273:Glucose Transporter Type 2; D007328:Insulin; D012333:RNA, Messenger; C495682:Slc2a2 protein, mouse; D019382:Human Growth Hormone; D001973:Bromodeoxyuridine; D005947:Glucose
keywords: FoxM1; human growth hormone; proliferation; transgene expression; β-cell