title: The proximal islet-specific glucose-6-phosphatase catalytic subunit-related protein autoantigen promoter is sufficient to initiate but not maintain transgene expression in mouse islets in vivo.
abstract: We have previously reported the discovery of an islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) that is predominantly expressed in islet beta-cells. IGRP has recently been identified as a major autoantigen in a mouse model of type 1 diabetes. The analysis of IGRP-chloramphenicol acetyltransferase (CAT) fusion gene expression in transiently transfected islet-derived hamster insulinoma tumor and betaTC-3 cells revealed that the promoter region located between -306 and +3 confers high-level reporter gene expression. To determine whether this same promoter region is sufficient to confer islet beta-cell-specific gene expression in vivo, it was ligated to a beta-galactosidase reporter gene, and transgenic mice expressing the resulting fusion gene were generated. In two independent founder lines, this -306 to +3 promoter region was sufficient to drive beta-galactosidase expression in newborn mouse islets, predominantly in beta-cells, which was initiated during the expected time in development, around embryonic day 12.5. However, unlike the endogenous IGRP gene, beta-galactosidase expression was also detected in the cerebellum. Moreover, beta-galactosidase expression was almost completely absent in adult mouse islets, suggesting that cis-acting elements elsewhere in the IGRP gene are required for determining appropriate IGRP tissue-specific expression and for the maintenance of IGRP gene expression in adult mice.
authors.affiliation: Department of Molecular Physiology and Biophysics, 761 PRB, Vanderbilt University Medical School, Nashville, TN 37232-0615, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Frigeri
authors.forename: Cyrus C
authors.initials: CC
authors.lastname: Martin
authors.forename: Christina A
authors.initials: CA
authors.lastname: Svitek
authors.forename: James K
authors.initials: JK
authors.lastname: Oeser
authors.forename: John C
authors.initials: JC
authors.lastname: Hutton
authors.forename: Maureen
authors.initials: M
authors.lastname: Gannon
authors.forename: Richard M
authors.initials: RM
authors.lastname: O'Brien
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D015870:Gene Expression / Q000502:physiology*; D017930:Genes, Reporter; D005952:Glucose-6-Phosphatase / Q000235:genetics* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D019076:Transgenes; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D005952:Glucose-6-Phosphatase; D018398:Homeodomain Proteins; D011506:Proteins; D014157:Transcription Factors; C117983:G6pc2 protein, mouse; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1