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- Title
Effect of Hedgehog Signal Intensity on Pancreas Morphogenesis.
- Authors
Nakayama, Shiho; Watada, Hirotaka; Fujitani, Yoshio; Igarashi, Yasuhiro; Iwashita, Noseki; Ikeda, Fuki; Kanno, Rei; Uchida, Toyoyoshi; Ogihara, Takeshi; Motoyama, Jun; Kawamori, Ryuzo
- Abstract
Embryonic Hedgehog signal is essential for proper tissue morphogenesis. Hedgehog ligands are expressed in whole endodermal epithelial cells except the region that will form pancreas at the early embryonic statge. Ectopic activation of Hedgehog signal in pancreatic primordia using several strategies resulted in the abnormal morphogenesis of pancreas, however according to previous reports, the ectopic activation of Hedgehog in pancreas results in various phenotypes which were not necessarily similar. We hypothesized that each phenotype would be determined by the intensity of Hedgehog signal and investigated the morphology of mice which have graded hedgehog signal intensity. In this study, we used Patched 1 (Ptc) mutants in this study. Ptc is a receptor of hedgehog ligands and is a negative regulator of hedgehog signal. Mes mice has the mutation of Ptc gene that results in a deletion of the most C-terminal cytoplasmic domain of the Ptc. We generated compound heterozygotes of Ptc-null and mes alleles. In this study, we investigated the pancreas morphology of Ptc+/+, +/mes, +/-, mes/mes, -/mes mice at embryonic day (e)10.5, e12.5, e15.5, e18.5. Quantitative RT-PCR methods identified that the expression of Glil mRNA that is known as a downstream target of Hedgehog signal in embryonic pancreas in each mice increased according to the estimated Hedgehog signal intensity. Immunohistochemical analysis identified PDX-1 expression level and the morphology of pancreas bud were not altered in each mice until e12.5. Although the expression of neurogenin3 is not altered, the number of insulin and glucagon positive cells decreased according to the increase in Hedgehog signal intensity. The number of amylase positive cells also decreased according to the increase in Hedgehog signal intensity. Among them, the number of insulin positive cells was the most sensitive to the increase in Hedgehog signal, because the significant decrease in the number of insulin positive cells was observed even in +/mes mice. On the other hand, the increase in mesenchymal cells was observed only in mes/mes and -/mes mice. Even in -/mes mice, transformation of pancreatic mesenchyme to duodenal mesoderm was not observed. In conclusion, the activation of Hedgehog signal results in the changes of cell number of all different cell types in pancreas, however, the threshold of hedgehog signal that results in dysmorphogenesis was variable according to cell types.
- Subjects
MORPHOGENESIS; EPITHELIAL cells; PANCREAS; DIABETES; MESSENGER RNA; MESENCHYME; LABORATORY mice
- Publication
Diabetes, 2007, Vol 56, pA416
- ISSN
0012-1797
- Publication type
Article