Cell Cycle Regulation of the Pdx1 Transcription Factor in Developing Pancreas and Insulin-Producing β Cells

Abstract

Current evidence indicates that proliferating β cells express lower levels of some functional cell identity genes, suggesting that proliferating cells are not optimally functional. Pdx1 is important for β-cell specification, function, and proliferation and is mutated in monogenic forms of diabetes. However, its regulation during the cell cycle is unknown. Here we examined Pdx1 protein expression in immortalized β cells, maternal mouse islets during pregnancy, and mouse embryonic pancreas. We demonstrate that Pdx1 localization and protein levels are highly dynamic. In non-mitotic cells, Pdx1 is not observed in constitutive heterochromatin, nucleoli, and most areas containing repressive epigenetic marks. At prophase, Pdx1 is enriched around the chromosomes prior to Ki67 coating the chromosome surface. Pdx1 uniformly localized in the cytoplasm at prometaphase and became enriched around the chromosomes again at the end of cell division, prior to nuclear envelope formation. Cells in S phase have lower Pdx1 levels than cells at earlier cell cycle stages, and over-expression of Pdx1 in INS-1 cells prevents progression toward G2, suggesting that cell cycle-dependent regulation of Pdx1 is required for completion of mitosis. Together, we find that Pdx1 localization and protein level are tightly regulated throughout the cell cycle. This dynamic regulation has implications for the dichotomous role of Pdx1 in β-cell function and proliferation.