GLIS3: A Critical Transcription Factor in Islet β-Cell Generation

Abstract

Understanding of pancreatic islet biology has greatly increased over the past few decades based in part on an increased understanding of the transcription factors that guide this process. One such transcription factor that has been increasingly tied to both β-cell development and the development of diabetes in humans is GLIS3. Genetic deletion of GLIS3 in mice and humans induces neonatal diabetes, while single nucleotide polymorphisms (SNPs) in GLIS3 have been associated with both Type 1 and Type 2 diabetes. As a significant progress has been made in understanding some of GLIS3's roles in pancreas development and diabetes, we sought to compare current knowledge on GLIS3 within the pancreas to that of other islet enriched transcription factors. While GLIS3 appears to regulate similar genes and pathways to other transcription factors, its unique roles in β-cell development and maturation make it a key target for future studies and therapy.

Keywords: GLIS3; development; diabetes; pancreas.

Figure 1

GLIS3 and its known interacting proteins. (A) The GLIS3 gene (NM_001042413) is composed of 11 exons, which produces (B) a 930 amino acid protein. Interactions have previously been identified with SUFU [20], ITCH [21], and PIASy/UBC9 [22] with either mouse or human GLIS3 protein. SUFU interaction inhibits GLIS3 polyubiquitination by the E3 ubiquitin ligase CUL3. The GLIS3 amino acids that are interacted with or modified are indicated.

Figure 2

GLIS3 expression during mouse endocrine development. GLIS3 protein is first detected in bipotent progenitor cells, and remains expressed in both ductal and endocrine lineages, before becoming restricted to β- and γ-cells.