Differentiation of early gut endoderm cells into the endocrine cells forming the pancreatic islets of Langerhans depends on a cascade of gene activation events controlled by transcription factors

The pancreas forms from dorsal and ventral buds that appear at the foregut-midgut junction starting at embryonic day (E)9.5 in the mouse. Over the subsequent 10 days of fetal development, these two apparently uniform clusters of epithelial cells differentiate into the cell types that compose the adult pancreas: the endocrine cells of the islets of Langerhans, the duct cells, and the exocrine cells (for reviews see Sander et al. (1997); Slack (1995)). The first detectable differentiated cells, starting at E9.5, are glucagon-expressing α cells followed sequentially by other islet cells: insulin-producing β cells, somatostatin-producing δ cells and pancreatic polypeptide-producing PP cells (Gittes and Rutter, 1992; Herrera et al., 1991; Pictet et al., 1972; Rall et al., 1973; Teitelman et al., 1993; Upchurch et al., 1994). Based on this order of appearance, a variety of transgenic experiments, and evidence that cells expressing more than one endocrine hormone are present early in pancreatic development, several models have been proposed to explain the developmental lineage of endocrine cells (Alpert et al., 1988; Herrera et al., 1994, 1991; Teitelman et al., 1993; Upchurch et al., 1994). These models have in common the supposition that the endocrine cells formed early in pancreatic development function as progenitors of the mature islet cells found later. This assumption has never been proved by direct lineage tracing. Alternatively, a population of undifferentiated precursor cells may persist, allowing for new islet cell formation throughout development. After E13, when ducts can first be distinguished, new endocrine cells appear adjacent to, or even embedded in the ducts (Githens, 1988; Herrera et al., 1991; 3533 Development 127, 3533-3542 (2000) Printed in Great Britain © The Company of Biologists Limited 2000 DEV6458