Expression of HNF-4alpha (MODY1), HNF-1beta (MODY5), and HNF-1alpha (MODY3) proteins in the developing mouse pancreas.

The type 1, 3, and 5 forms of maturity-onset diabetes of the young (MODY) are caused by mutations of the genes encoding hepatocyte nuclear factor (HNF)-4alpha, HNF-1alpha, and HNF-1beta, respectively [Yamagata, K., Oda, N., Kaisaki, P.J., Menzel, S., Furuta, H., Vaxillaire, M., et al., 1996a. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature 384, 455-458; Yamagata, K., Furuta, H., Oda, N., Kaisaki, P.J., Menzel, S., Cox, N.J., et al., 1996b. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature 384, 458-460; Horikawa, Y., Iwasaki, N., Hara, M., Furuta, H., Hinokio, Y., Cockburn, B.N. et al., 1997. Mutation in hepatocyte nuclear factor-1beta gene (TCF2) associated with MODY. Nat. Genet. 17, 384-385]. Among these transcription factors, the pattern of HNF-4alpha expression during pancreatic differentiation remains largely unknown. We performed an immunohistochemical study to investigate its expression in comparison with the expression of HNF-1alpha and HNF-1beta. We found considerable variation in the level of HNF-4alpha expression by the individual epithelial cells in the pancreatic buds on E9.5. HNF-4alpha and HNF-1beta were initially expressed by Pdx1(+) common progenitor cells and neurogenin3(+) (Ngn3(+)) endocrine precursor cells during the first transition, but expression of HNF-1beta and either HNF-4alpha or HNF-1alpha became complementary around the end of the second transition (E15.5). In the mature pancreas, HNF-4alpha was expressed by glucagon-positive alpha-cells, insulin-positive beta-cells, somatostatin-positive delta-cells, and pancreatic polypeptide-positive PP-cells, as well as by pancreatic exocrine cells and ductal cells. Most of the HNF-4alpha(+) cells were also positive for HNF-1alpha, but HNF-4alpha expression in some non-beta-cells was remarkably high, and this was not paralleled by high HNF-1alpha expression. These results indicate that the expression of MODY proteins in each of the pancreatic cell types is strictly regulated in accordance with the status of differentiation during pancreatic organogenesis.