Neurog3-dependent pancreas dysgenesis causes ectopic pancreas in Hes1 mutant mice.
| Autor: | Jørgensen MC; NNF Center for Stem Cell Biology (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark., de Lichtenberg KH; NNF Center for Stem Cell Biology (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark., Collin CA; NNF Center for Stem Cell Biology (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark., Klinck R; Novo Nordisk A/S, Department of User Research and Communication, Brennum Park 1, DK-3400 Hillerød, Denmark., Ekberg JH; NNF Center for Basic Metabolic Research, Section for Metabolic Receptology, Laboratory for Molecular Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark., Engelstoft MS; NNF Center for Basic Metabolic Research, Section for Metabolic Receptology, Laboratory for Molecular Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark., Lickert H; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany., Serup P; NNF Center for Stem Cell Biology (DanStem), Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark palle.serup@sund.ku.dk. |
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| Jazyk: | angličtina |
| Zdroj: | Development (Cambridge, England) [Development] 2018 Sep 03; Vol. 145 (17). Date of Electronic Publication: 2018 Sep 03. |
| DOI: | 10.1242/dev.163568 |
| Abstrakt: | Mutations in Hes1 , a target gene of the Notch signalling pathway, lead to ectopic pancreas by a poorly described mechanism. Here, we use genetic inactivation of Hes1 combined with lineage tracing and live imaging to reveal an endodermal requirement for Hes1, and show that ectopic pancreas tissue is derived from the dorsal pancreas primordium. RNA-seq analysis of sorted E10.5 Hes1 +/+ and Hes1 -/- Pdx1-GFP + cells suggested that upregulation of endocrine lineage genes in Hes1 -/- embryos was the major defect and, accordingly, early pancreas morphogenesis was normalized, and the ectopic pancreas phenotype suppressed, in Hes1 -/- Neurog3 -/- embryos. In Mib1 mutants, we found a near total depletion of dorsal progenitors, which was replaced by an anterior Gcg + extension. Together, our results demonstrate that aberrant morphogenesis is the cause of ectopic pancreas and that a part of the endocrine differentiation program is mechanistically involved in the dysgenesis. Our results suggest that the ratio of endocrine lineage to progenitor cells is important for morphogenesis and that a strong endocrinogenic phenotype without complete progenitor depletion, as seen in Hes1 mutants, provokes an extreme dysgenesis that causes ectopic pancreas. Competing Interests: Competing interestsThe authors declare no competing or financial interests. (© 2018. Published by The Company of Biologists Ltd.) |
| Databáze: | MEDLINE |
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