Expression of HNF-4α (MODY1), HNF-1β (MODY5), and HNF-1α (MODY3) proteins in the developing mouse pancreas

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• 作者：Takao Nammo ; Kazuya Yamagata ; Toshiya Tanaka ; Tatsuhiko Kodama ; Frances M. Sladek ; Kenji Fukui ; Fumie Katsube ; Yoshifumi Sato ; Jun-ichiro Miyagawa ; Iichiro Shimomura
• 关键词：HNF-4α ; HNF-1β ; HNF-1α ; MODY1 ; MODY3 ; MODY5 ; Diabetes ; Mouse ; Pancreas ; Transcription factor ; Ngn3 ; Pdx1 ; Isl1 ; Nkx2.2 ; Insulin ; Glucagon ; Somatostatin ; Pancreatic polypeptide ; Amylase
• 刊名：Gene Expression Patterns
• 出版年：2008
• 出版时间：January 2008
• 年：2008
• 卷：8
• 期：2
• 页码：96-106
• 全文大小：7978 K

文摘

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)-4α, HNF-1α, and HNF-1β, respectively [Yamagata, K., Oda, N., Kaisaki, P.J., Menzel, S., Furuta, H., Vaxillaire, M., et al., 1996a. Mutations in the hepatocyte nuclear factor-1α 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-4α 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-1β gene (TCF2) associated with MODY. Nat. Genet. 17, 384–385]. Among these transcription factors, the pattern of HNF-4α expression during pancreatic differentiation remains largely unknown. We performed an immunohistochemical study to investigate its expression in comparison with the expression of HNF-1α and HNF-1β. We found considerable variation in the level of HNF-4α expression by the individual epithelial cells in the pancreatic buds on E9.5. HNF-4α and HNF-1β were initially expressed by Pdx1⁺ common progenitor cells and neurogenin3⁺ (Ngn3⁺) endocrine precursor cells during the first transition, but expression of HNF-1β and either HNF-4α or HNF-1α became complementary around the end of the second transition (E15.5). In the mature pancreas, HNF-4α was expressed by glucagon-positive α-cells, insulin-positive β-cells, somatostatin-positive δ-cells, and pancreatic polypeptide-positive PP-cells, as well as by pancreatic exocrine cells and ductal cells. Most of the HNF-4α⁺ cells were also positive for HNF-1α, but HNF-4α expression in some non-β-cells was remarkably high, and this was not paralleled by high HNF-1α 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.