Recent studies have outlined a major role for the forkhead protein FOXOl in (3- cell differentiation, proliferation, and stress resistance in the adult islet. The objective of this study was to characterize the expression pattern and function of FOXOl during human fetal islet cell development (8 to 21 weeks of fetal age). Using immunostaining, FOXOl co-localized with ductal and endocrine cell markers, in addition to PDX-1 and NGN3 transcription factors throughout development. In vitro, nuclear export of FOXOl occurred in islet-epithelial cell clusters (18 to 21 wks) exposed to high insulin concentrations in a PI3-Kinase/AKT dependent manner. Cells transfected with FOXOl siRNA demonstrated an up-regulation in NGN3 and NKX6-1 mRNA levels and protein cellular distribution in parallel with an increase in the (3-cell population, a down- regulation in the NGN3 inhibitory factor HES1, and no effect on PDX-1. In conclusion, these results outline a role by which FOXOl may contribute to islet cell development
