The role of GLIS3 in human pancreas development and diabetes mellitus

• Applicant: Dr. Jifeng Liu
• Subject Area: Developmental Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 523926206

Diabetes mellitus is a group of chronic metabolic diseases characterized by high blood sugar levels. Both genetic and environmental factors that affect insulin secretion or the response of cells to insulin may lead to the onset of diabetes mellitus. The krüppel-like zinc finger transcription factor Gli-similar 3 (GLIS3) was found to be a diabetes-associated gene since patients with homozygous or compound heterozygous mutations in GLIS3 exhibit a syndrome of neonatal diabetes and congenital hypothyroidism (NDH). In addition, GLIS3 mutant patients also display other clinical features in multiple organs, such as a cystic change in the head of the pancreas, cysts in the kidney, or fibrosis in the liver. To understand the mechanisms of the association of GLIS3 mutations with neonatal diabetes, studies in mice have found that Glis3 can regulate pancreatic β cell differentiation, protect β cells from apoptosis and keep β-cell function. A two-dimensional (2D) study in humans has also revealed that GLIS3 can protect pancreatic progenitors and β-cells from apoptosis. However, the role of GLIS3 in human pancreatic ductal and endocrine differentiation, as well as in β-cell function, is still largely unknown. In this project, using a human embryonic stem cell-derived 3D pancreatic sphere model, we have found that GLIS3 inactivation promotes cyst formation, which recapitulates the cystic phenotype observed in Glis3 mutant mice and some GLIS3 mutant patients. In addition, transcriptome analysis has revealed that the reduced ductal differentiation, increased proliferation, and decreased cilia program may contribute to this phenotype. Next, we will perform experiments to understand more mechanisms about why GLIS3 mutations promote cyst formation and the role of GLIS3 in regulating ductal differentiation, endocrine differentiation, and maintaining β cell function.

• DFG Programme: WBP Position