title: Bicaudal C1 promotes pancreatic NEUROG3+ endocrine progenitor differentiation and ductal morphogenesis.
abstract: In human, mutations in bicaudal C1 (BICC1), an RNA binding protein, have been identified in patients with kidney dysplasia. Deletion of Bicc1 in mouse leads to left-right asymmetry randomization and renal cysts. Here, we show that BICC1 is also expressed in both the pancreatic progenitor cells that line the ducts during development, and in the ducts after birth, but not in differentiated endocrine or acinar cells. Genetic inactivation of Bicc1 leads to ductal cell over-proliferation and cyst formation. Transcriptome comparison between WT and Bicc1 KO pancreata, before the phenotype onset, reveals that PKD2 functions downstream of BICC1 in preventing cyst formation in the pancreas. Moreover, the analysis highlights immune cell infiltration and stromal reaction developing early in the pancreas of Bicc1 knockout mice. In addition to these functions in duct morphogenesis, BICC1 regulates NEUROG3(+) endocrine progenitor production. Its deletion leads to a late but sustained endocrine progenitor decrease, resulting in a 50% reduction of endocrine cells. We show that BICC1 functions downstream of ONECUT1 in the pathway controlling both NEUROG3(+) endocrine cell production and ductal morphogenesis, and suggest a new candidate gene for syndromes associating kidney dysplasia with pancreatic disorders, including diabetes.
authors.affiliation: DanStem, University of Copenhagen, 3B Blegdamsvej, Copenhagen N DK-2200, Denmark ISREC, Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Lemaire
authors.affiliation: ISREC, Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
authors.forename: Joan
authors.initials: J
authors.lastname: Goulley
authors.affiliation: DanStem, University of Copenhagen, 3B Blegdamsvej, Copenhagen N DK-2200, Denmark ISREC, Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
authors.forename: Yung Hae
authors.initials: YH
authors.lastname: Kim
authors.affiliation: BBCF, Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
authors.forename: Solenne
authors.initials: S
authors.lastname: Carat
authors.affiliation: de Duve Institute, Université catholique de Louvain, Brussels B-1200, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Jacquemin
authors.affiliation: BBCF, Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
authors.forename: Jacques
authors.initials: J
authors.lastname: Rougemont
authors.affiliation: ISREC, Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Constam
authors.affiliation: DanStem, University of Copenhagen, 3B Blegdamsvej, Copenhagen N DK-2200, Denmark ISREC, Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland anne.grapin-botton@sund.ku.dk.
authors.forename: Anne
authors.initials: A
authors.lastname: Grapin-Botton
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D005455:Fluorescent Antibody Technique; D005838:Genotype; D051559:Hepatocyte Nuclear Factor 6 / Q000235:genetics / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051559:Hepatocyte Nuclear Factor 6; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D050396:TRPP Cation Channels; C540667:Bicc1 protein, mouse; C407737:Neurog3 protein, mouse; C496606:Onecut1 protein, mouse
keywords: Beta cell; Cysts; Diabetes; Differentiation; Embryo; Endocrine; Insulin; MODY5; Pancreas; Progenitors; RNA-binding protein