Diabetes and pancreatic tumours in transgenic mice expressing Pa x 6

Aims/hypothesis. Both endocrine and exocrine cells of the pancreas differen tiate from epithelial cells of primitive pancreatic ducts, and four types o f pancreatic islet cells (alpha, beta, delta, and PP cells) are derived fro m the common pluripotent precursor cells. Although Pa x 6 is expressed in a ll islet cells, Pa x 4 is detected only in beta cells. In homozygous Pa x 4 -null mice, beta cells are absent, whereas the number of alpha cells is inc reased. Therefore, we hypothesized that the balance of Pa x 4 and 6 is one of the determinants by which the common progenitor cells differentiate into alpha or beta cells. Methods. To change this balance, we generated transgenic mice overexpressin g Pa x 6 driven by the insulin promoter or the PDX1 promoter. Results. In both types of transgenic mice, normal development of beta cells was disturbed, resulting in apoptosis of beta cells and diabetes. In Insul in/Pa x 6-Tg mice, beta cells were specifically affected, whereas in PDX/Pa x 6-Tg mice, developmental abnormalities involved the whole pancreas inclu ding hypoplasia of the exocrine pancreas. Furthermore, PDX/Pa x 6-Tg mice e xperienced proliferation of both ductal epithelia and islet cells and subse quent cystic adenoma of the pancreas. Conclusion/interpretation. These findings suggest that Pa x 6 promotes the growth of ductal epithelia and endocrine progenitor cells and that the supp ression of Pa x 6 is necessary for the normal development of beta cells and the exocrine pancreas.