title: Mesenchymal Hox6 function is required for mouse pancreatic endocrine cell differentiation.
abstract: Despite significant advances in our understanding of pancreatic endocrine cell development, the function of the pancreatic mesodermal niche in this process is poorly understood. Here we report a novel role for mouse Hox6 genes in pancreatic organogenesis. Hox6 genes are expressed exclusively in the mesoderm of the developing pancreas. Genetic loss of all three Hox6 paralogs (Hoxa6, Hoxb6 and Hoxc6) leads to a dramatic loss of endoderm-derived endocrine cells, including insulin-secreting β-cells, and to mild delays and disruptions in pancreatic branching and exocrine differentiation. Ngn3-expressing pan-endocrine progenitor cells are specified normally in Hox6 mutant pancreata, but fail to mature into hormone-producing cells. Reduced expression of Wnt5a is observed in mutant pancreatic mesenchyme, leading to subsequent loss of expression of the crucial Wnt inhibitors Sfrp3 and Dkk1 in endocrine progenitor cells. These results reveal a key role for Hox6 genes in establishing Wnt mesenchymal-epithelial crosstalk in pancreatic development.
authors.affiliation: Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan, Ann Arbor, MI 48109-2200, USA Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109-2200, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Larsen
authors.affiliation: Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan, Ann Arbor, MI 48109-2200, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Hrycaj
authors.affiliation: Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan, Ann Arbor, MI 48109-2200, USA.
authors.forename: Micaleah
authors.initials: M
authors.lastname: Newman
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-2200, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan, Ann Arbor, MI 48109-2200, USA Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109-2200, USA Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-2200, USA dwellik@umich.edu.
authors.forename: Deneen M
authors.initials: DM
authors.lastname: Wellik
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D055098:Endocrine Cells / Q000378:metabolism / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D018398:Homeodomain Proteins / Q000378:metabolism*; D017403:In Situ Hybridization; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D038081:Organogenesis / Q000502:physiology*; D010179:Pancreas / Q000166:cytology / Q000196:embryology*; D060888:Real-Time Polymerase Chain Reaction; D013629:Tamoxifen
chemical_list: D018398:Homeodomain Proteins; C000605398:Hox6 protein, mouse; D013629:Tamoxifen
keywords: Endocrine cells; Hox genes; Mesenchymal-epithelial crosstalk; Mouse; Pancreatic development; Wnt signaling