title: Retinol Dehydrogenase-10 Regulates Pancreas Organogenesis and Endocrine Cell Differentiation via Paracrine Retinoic Acid Signaling.
abstract: Vitamin A-derived retinoic acid (RA) signals are critical for the development of several organs, including the pancreas. However, the tissue-specific control of RA synthesis in organ and cell lineage development has only poorly been addressed in vivo. Here, we show that retinol dehydrogenase-10 (Rdh10), a key enzyme in embryonic RA production, has important functions in pancreas organogenesis and endocrine cell differentiation. Rdh10 was expressed in the developing pancreas epithelium and surrounding mesenchyme. Rdh10 null mutant mouse embryos exhibited dorsal pancreas agenesis and a hypoplastic ventral pancreas with retarded tubulogenesis and branching. Conditional disruption of Rdh10 from the endoderm caused increased mortality, reduced body weight, and lowered blood glucose levels after birth. Endodermal Rdh10 deficiency led to a smaller dorsal pancreas with a reduced density of early glucagon+and insulin+cells. During the secondary transition, the reduction of Neurogenin3+endocrine progenitors in the mutant dorsal pancreas accounted for fewer α- and β-cells. Changes in the expression of α- and β-cell-specific transcription factors indicated that Rdh10 might also participate in the terminal differentiation of endocrine cells. Together, our results highlight the importance of both mesenchymal and epithelial Rdh10 for pancreogenesis and the first wave of endocrine cell differentiation. We further propose a model in which the Rdh10-expressing exocrine tissue acts as an essential source of RA signals in the second wave of endocrine cell differentiation.
authors.affiliation: Lund Stem Cell Center (I.Arr., M.C., D.I., J.S., N.G., J.K.J., T.S., M.M., I.Art., E.M.P.), Lund University, SE-22184 Lund, Sweden; The Danish Stem Cell Center (H.S.), University of Copenhagen, DK-2200 Copenhagen, Denmark; and Department of Pharmacology (L.M.), University of Oxford, OX1 3QT Oxford, United Kingdom.
authors.forename: Igor
authors.initials: I
authors.lastname: Arregi
authors.affiliation: Lund Stem Cell Center (I.Arr., M.C., D.I., J.S., N.G., J.K.J., T.S., M.M., I.Art., E.M.P.), Lund University, SE-22184 Lund, Sweden; The Danish Stem Cell Center (H.S.), University of Copenhagen, DK-2200 Copenhagen, Denmark; and Department of Pharmacology (L.M.), University of Oxford, OX1 3QT Oxford, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Climent
authors.affiliation: Lund Stem Cell Center (I.Arr., M.C., D.I., J.S., N.G., J.K.J., T.S., M.M., I.Art., E.M.P.), Lund University, SE-22184 Lund, Sweden; The Danish Stem Cell Center (H.S.), University of Copenhagen, DK-2200 Copenhagen, Denmark; and Department of Pharmacology (L.M.), University of Oxford, OX1 3QT Oxford, United Kingdom.
authors.forename: Dobromir
authors.initials: D
authors.lastname: Iliev
authors.affiliation: Lund Stem Cell Center (I.Arr., M.C., D.I., J.S., N.G., J.K.J., T.S., M.M., I.Art., E.M.P.), Lund University, SE-22184 Lund, Sweden; The Danish Stem Cell Center (H.S.), University of Copenhagen, DK-2200 Copenhagen, Denmark; and Department of Pharmacology (L.M.), University of Oxford, OX1 3QT Oxford, United Kingdom.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Strasser
authors.affiliation: Lund Stem Cell Center (I.Arr., M.C., D.I., J.S., N.G., J.K.J., T.S., M.M., I.Art., E.M.P.), Lund University, SE-22184 Lund, Sweden; The Danish Stem Cell Center (H.S.), University of Copenhagen, DK-2200 Copenhagen, Denmark; and Department of Pharmacology (L.M.), University of Oxford, OX1 3QT Oxford, United Kingdom.
authors.forename: Nadège
authors.initials: N
authors.lastname: Gouignard
authors.affiliation: Lund Stem Cell Center (I.Arr., M.C., D.I., J.S., N.G., J.K.J., T.S., M.M., I.Art., E.M.P.), Lund University, SE-22184 Lund, Sweden; The Danish Stem Cell Center (H.S.), University of Copenhagen, DK-2200 Copenhagen, Denmark; and Department of Pharmacology (L.M.), University of Oxford, OX1 3QT Oxford, United Kingdom.
authors.forename: Jenny K
authors.initials: JK
authors.lastname: Johansson
authors.affiliation: Lund Stem Cell Center (I.Arr., M.C., D.I., J.S., N.G., J.K.J., T.S., M.M., I.Art., E.M.P.), Lund University, SE-22184 Lund, Sweden; The Danish Stem Cell Center (H.S.), University of Copenhagen, DK-2200 Copenhagen, Denmark; and Department of Pharmacology (L.M.), University of Oxford, OX1 3QT Oxford, United Kingdom.
authors.forename: Tania
authors.initials: T
authors.lastname: Singh
authors.affiliation: Lund Stem Cell Center (I.Arr., M.C., D.I., J.S., N.G., J.K.J., T.S., M.M., I.Art., E.M.P.), Lund University, SE-22184 Lund, Sweden; The Danish Stem Cell Center (H.S.), University of Copenhagen, DK-2200 Copenhagen, Denmark; and Department of Pharmacology (L.M.), University of Oxford, OX1 3QT Oxford, United Kingdom.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Mazur
authors.affiliation: Lund Stem Cell Center (I.Arr., M.C., D.I., J.S., N.G., J.K.J., T.S., M.M., I.Art., E.M.P.), Lund University, SE-22184 Lund, Sweden; The Danish Stem Cell Center (H.S.), University of Copenhagen, DK-2200 Copenhagen, Denmark; and Department of Pharmacology (L.M.), University of Oxford, OX1 3QT Oxford, United Kingdom.
authors.forename: Henrik
authors.initials: H
authors.lastname: Semb
authors.affiliation: Lund Stem Cell Center (I.Arr., M.C., D.I., J.S., N.G., J.K.J., T.S., M.M., I.Art., E.M.P.), Lund University, SE-22184 Lund, Sweden; The Danish Stem Cell Center (H.S.), University of Copenhagen, DK-2200 Copenhagen, Denmark; and Department of Pharmacology (L.M.), University of Oxford, OX1 3QT Oxford, United Kingdom.
authors.forename: Isabella
authors.initials: I
authors.lastname: Artner
authors.affiliation: Lund Stem Cell Center (I.Arr., M.C., D.I., J.S., N.G., J.K.J., T.S., M.M., I.Art., E.M.P.), Lund University, SE-22184 Lund, Sweden; The Danish Stem Cell Center (H.S.), University of Copenhagen, DK-2200 Copenhagen, Denmark; and Department of Pharmacology (L.M.), University of Oxford, OX1 3QT Oxford, United Kingdom.
authors.forename: Liliana
authors.initials: L
authors.lastname: Minichiello
authors.affiliation: Lund Stem Cell Center (I.Arr., M.C., D.I., J.S., N.G., J.K.J., T.S., M.M., I.Art., E.M.P.), Lund University, SE-22184 Lund, Sweden; The Danish Stem Cell Center (H.S.), University of Copenhagen, DK-2200 Copenhagen, Denmark; and Department of Pharmacology (L.M.), University of Oxford, OX1 3QT Oxford, United Kingdom.
authors.forename: Edgar M
authors.initials: EM
authors.lastname: Pera
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology*; D000013:Congenital Abnormalities / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D038081:Organogenesis / Q000502:physiology*; D010179:Pancreas / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism; D019899:Paracrine Communication / Q000502:physiology*; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D014212:Tretinoin; D000429:Alcohol Oxidoreductases; C113992:trans-retinol dehydrogenase