Understanding the extrinsic and intrinsic signals involved in pancreas and β-cell development: from endoderm to β cells.

Abstract

To summarize recent progress in understanding of the extrinsic and intrinsic signals directing pancreas development from early endoderm. The pancreatic mesoderm was shown not only to play a permissive role in pancreas determination but also to control endocrine commitment and maturation through the interplay between Notch and fibroblast growth factor signaling. The requirement of Wnt (wingless-type)/β-catenin signaling in the expansion of the acinar cell lineage, and the spatial-temporal specificity of PDX1 (pancreatic and duodenal homeobox) activity, which is needed for proper acinar development, were also demonstrated. A novel factor, IA1 (insulinoma-associated 1), was identified as an endocrine marker downstream of Ngn3 (neurogenin); MAFB (musculo-aponeurotic fibrosarcoma) was shown to be a marker of α-cell and β-cell precursors, and ARX (aristaless-related homeobox), a marker of α-cell progenitors, was revealed to directly antagonize PAX4 (paired homeobox) in determining α-cell and β-cell lineages. Cell fate specification results from combined effects of extrinsic and intrinsic regulators and sensitivity of target cells to them, which vary depending on the precise stage of cell commitment or differentiation. Knowledge of the hierarchy of the different factors influencing pancreas development will aid in developing new cell therapies to treat diabetes.