Differential Gene Dosage Effects of Diabetes-Associated Gene GLIS3 in Pancreatic β Cell Differentiation and Function.
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 β cell-specific Glis3fl/fl/Pdx1CreERT mice, but not in TAM-treated Glis3fl/fl/MipCreERT mice. Furthermore, we generated constitutive β 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 β 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 β cell dysfunction in people.
Division of Endocrinology, Department of Medicine, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio 44109.
Yisheng
Y
Yang
Division of Endocrinology, Department of Medicine, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio 44109.
Sean P
SP
Bush
Division of Endocrinology, Department of Medicine, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio 44109.|Department of Anesthesiology, First People's Hospital of Foshan and Foshan Hospital of Sun Yat-sen University, Guangdong, China 528300; and.
Xianjie
X
Wen
Division of Endocrinology, Department of Medicine, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio 44109.
Wei
W
Cao
Diabetes and Endocrinology Research Center, Division of Diabetes, Endocrinology, and Metabolism, Departments of Medicine, Molecular and Cellular Biology, Biochemistry and Molecular Biology, and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030.
Lawrence
L
Chan
D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D003409:Congenital Hypothyroidism / Q000235:genetics; D004268:DNA-Binding Proteins; D003921:Diabetes Mellitus, Experimental / Q000209:etiology*; D005260:Female; D018628:Gene Dosage; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011247:Pregnancy; D012097:Repressor Proteins / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D007328:Insulin; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; C478000:Glis3 protein, mouse; C407737:Neurog3 protein, mouse