| First Author | Yang Y | Year | 2017 |
| Journal | Endocrinology | Volume | 158 |
| Issue | 1 | Pages | 9-20 |
| PubMed ID | 27813676 | Mgi Jnum | J:245502 |
| Mgi Id | MGI:5916314 | Doi | 10.1210/en.2016-1541 |
| Citation | Yang Y, et al. (2017) Differential Gene Dosage Effects of Diabetes-Associated Gene GLIS3 in Pancreatic beta Cell Differentiation and Function. Endocrinology 158(1):9-20 |
| abstractText | Mutations of GLI-similar 3 (GLIS3) underlie a neonatal diabetes syndrome. Genome-wide association studies revealed that GLIS3 variants are associated with both common type 1 and type 2 diabetes. Global Glis3-deficient (Glis3-/-) mice die of severe diabetes shortly after birth. GLIS3 controls islet differentiation by transactivating neurogenin 3 (Ngn3). To unravel the function of Glis3 in adults, we generated inducible global Glis3-deficient mice (Glis3fl/fl/RosaCreERT2). Tamoxifen (TAM)-treated Glis3fl/fl/RosaCreERT2 mice developed severe diabetes, which was reproduced in TAM-treated beta cell-specific Glis3fl/fl/Pdx1CreERT mice, but not in TAM-treated Glis3fl/fl/MipCreERT mice. Furthermore, we generated constitutive beta cell- or pancreas-specific Glis3-deficient mice using either RipCre (Glis3fl/fl/RipCre) or Pdx1Cre (Glis3fl/fl/Pdx1Cre) coexpressing mice. We observed that, remarkably, neither type of beta cell- or pancreas-specific Glis3-deficient mice phenocopied the lethal neonatal diabetes observed in Glis3-/- mice. All Glis3fl/fl/RipCre mice survived to adulthood with normal glucose tolerance. Thirty percent of Glis3fl/fl/Pdx1Cre mice developed severe diabetes at 3 to 4 weeks of age, whereas 55% of them developed mild diabetes with age. In contrast to the >90% reduction of Ngn3 and near-total absence of insulin (Ins) in the embryonic pancreas of Glis3-/- mice, we found only 75%-80% reduction of Ngn3 and Ins messenger RNA or protein expression in the fetal pancreas of Glis3fl/fl/Pdx1Cre mice. The expression levels of Ngn3 and Ins correlated negatively with the extent of Cre-mediated Glis3 deletion. These mouse models are powerful tools to decipher Glis3 gene dosage effects and the role of GLIS3 mutations/variants in a spectrum of beta cell dysfunction in people. |
