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 β-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 βTC-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 β-cell-specific gene expression in vivo, it was ligated to a β-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 β-galactosidase expression in newborn mouse islets, predominantly in β-cells, which was initiated during the expected time in development, around embryonic day 12.5. However, unlike the endogenous IGRP gene, β-galactosidase expression was also detected in the cerebellum. Moreover, β-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.