title: Ngn3(+) endocrine progenitor cells control the fate and morphogenesis of pancreatic ductal epithelium.
abstract: During pancreas development, endocrine and exocrine cells arise from a common multipotent progenitor pool. How these cell fate decisions are coordinated with tissue morphogenesis is poorly understood. Here we have examined ductal morphology, endocrine progenitor cell fate and Notch signaling in Ngn3(-/-) mice, which do not produce islet cells. Ngn3 deficiency results in reduced branching and enlarged pancreatic duct-like structures, concomitant with Ngn3 promoter activation throughout the ductal epithelium and reduced Notch signaling. Conversely, forced generation of surplus endocrine progenitor cells causes reduced duct caliber and an excessive number of tip cells. Thus, endocrine progenitor cells normally provide a feedback signal to adjacent multipotent ductal progenitor cells that activates Notch signaling, inhibits further endocrine differentiation and promotes proper morphogenesis. These results uncover a novel layer of regulation coordinating pancreas morphogenesis and endocrine/exocrine differentiation, and suggest ways to enhance the yield of beta cells from stem cells.
authors: Department of Developmental Biology and Cancer Research, The institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors: Judith
authors: J
authors: Magenheim
authors: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors: Allon M
authors: AM
authors: Klein
authors: Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors: Ben Z
authors: BZ
authors: Stanger
authors: Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, 69978 Ramat Aviv, Tel Aviv, Israel.
authors: Ruth
authors: R
authors: Ashery-Padan
authors: Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Beatriz
authors: B
authors: Sosa-Pineda
authors: Program in Developmental Biology and Department of Cell and Developmental Biology, Center for Stem Cell Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Guoqiang
authors: G
authors: Gu
authors: Department of Developmental Biology and Cancer Research, The institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel. Electronic address: yuvald@ekmd.huji.ac.il.
authors: Yuval
authors: Y
authors: Dor
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D019070:Cell Lineage; D004847:Epithelial Cells / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D010183:Pancreatic Ducts / Q000166:cytology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; C407737:Neurog3 protein, mouse