The key functions of the pancreas are to regulate digestion and sugar metabolism. Our desire to understand the development of this organ is driven not only by the need to understand organ formation, but also by the hope that we can recapitulate it in vitro, thus creating a supply of insulin-producing cells for diabetes therapy. An important step in this direction is now provided by Kawaguchi and colleagues, who report that the pancreatic transcription factor Ptf1a is required in mice to commit cells to the pancreatic fate and for their subsequent proliferation and differentiation.

Ptf1a was previously implicated in the development of the exocrine pancreas — the portion that is responsible for secreting digestive enzymes. Little was known about Ptf1a-expressing cells during early pancreatic development, so the authors did careful recombination-based lineage tracing in mice in which the expression of a lacZ reporter was activated by the endogenous Ptf1a promoter in normal and in Ptf1a-deficient mice.

Because the activated lacZ allele is expressed independently of cell fate, the progeny of cells in which the Ptf1a promoter had been activated could be definitively identified. In the normal pancreas, Kawaguchi et al. found that cells from both the exocrine and the endocrine — hormone-producing — pancreas express Ptf1a early in their lineage history. Most importantly, they saw that Ptf1a deficiency causes large numbers of lacZ-expressing cells to appear in the intestinal epithelium. So, the presence or absence of Ptf1a seems to be crucial in determining how endodermal progenitors choose between organ fates.

As another test of whether Ptf1a is expressed in all pancreatic precursors, the authors used its promoter to drive the expression of Pdx1 — a gene that is essential for pancreas formation. It turned out that Ptf1a-driven expression of Pdx1 was sufficient to restore the formation of all pancreatic lineages in Pdx1−/− mice, indicating that Ptf1a might be expressed early in all pancreatic precursors. Immunohistochemical time-course studies confirmed that this expression is subsequently turned off in endocrine cells.

The authors' demonstration that Ptf1a expression is essential for cells to adopt and maintain pancreatic fate has important therapeutic potential. So far, attempts to form pancreatic precursors in vitro, which could be used to treat diabetes using transplantation therapy, have failed. It might be that with their discovery of the early role of Ptf1a, Kawaguchi and colleagues have uncovered one of the missing key players.