Defining the cell lineages of the islets of Langerhans using transgenic mice

In this Special Issue of the Int. J. Dev. Biol., we summarize our own studies on the development of the mouse endocrine pancreas, with special emphasis on the cell lineage relationships between the four islet cell types. Considerable knowledge concerning the ontogeny of the endocrine pancreas has been gained in recent years, mainly through the use of two complementary genetic approaches in mice: gene inactivation and genetic labelling of precursor cells. However, neither gene inactivation in KO mice nor co-localisation of hormones in single cells during development can be taken as evidence for cell lineage relationships among different cell types. The beta-cell lineage analysis was started by selectively ablating specific islet cell types in transgenic mice. We used the diphtheria toxin A subunit coding region under the control of insulin, glucagon or pancreatic polypeptide (PP) promoters, in order to eliminate insulin-, glucagon- or PP-expressing cells, respectively. Contrary to the common view, we demonstrated that glucagon cells are not precursors of insulin-producing cells. These results were in addition the first evidence of a close ontogenetic relationship between insulin and somatostatin cells. We pursued these analyses using a novel, more subtle approach: progenitor cell labelling through the expression of Cre recombinase in doubly transgenic mice. We were able to unequivocally establish that 1) adult glucagon- and insulin-producing cells derive from precursors which have never transcribed insulin or glucagon, respectively; 2) insulin cell progenitors, but not glucagon cell progenitors transcribe the PP gene and 3) adult glucagon cells derive from progenitors which do express pdx1.