title: In Vivo Senescence in the Sbds-Deficient Murine Pancreas: Cell-Type Specific Consequences of Translation Insufficiency.
abstract: Genetic models of ribosome dysfunction show selective organ failure, highlighting a gap in our understanding of cell-type specific responses to translation insufficiency. Translation defects underlie a growing list of inherited and acquired cancer-predisposition syndromes referred to as ribosomopathies. We sought to identify molecular mechanisms underlying organ failure in a recessive ribosomopathy, with particular emphasis on the pancreas, an organ with a high and reiterative requirement for protein synthesis. Biallelic loss of function mutations in SBDS are associated with the ribosomopathy Shwachman-Diamond syndrome, which is typified by pancreatic dysfunction, bone marrow failure, skeletal abnormalities and neurological phenotypes. Targeted disruption of Sbds in the murine pancreas resulted in p53 stabilization early in the postnatal period, specifically in acinar cells. Decreased Myc expression was observed and atrophy of the adult SDS pancreas could be explained by the senescence of acinar cells, characterized by induction of Tgfβ, p15(Ink4b) and components of the senescence-associated secretory program. This is the first report of senescence, a tumour suppression mechanism, in association with SDS or in response to a ribosomopathy. Genetic ablation of p53 largely resolved digestive enzyme synthesis and acinar compartment hypoplasia, but resulted in decreased cell size, a hallmark of decreased translation capacity. Moreover, p53 ablation resulted in expression of acinar dedifferentiation markers and extensive apoptosis. Our findings indicate a protective role for p53 and senescence in response to Sbds ablation in the pancreas. In contrast to the pancreas, the Tgfβ molecular signature was not detected in fetal bone marrow, liver or brain of mouse models with constitutive Sbds ablation. Nevertheless, as observed with the adult pancreas phenotype, disease phenotypes of embryonic tissues, including marked neuronal cell death due to apoptosis, were determined to be p53-dependent. Our findings therefore point to cell/tissue-specific responses to p53-activation that include distinction between apoptosis and senescence pathways, in the context of translation disruption.
authors.affiliation: Program in Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: Marina E
authors.initials: ME
authors.lastname: Tourlakis
authors.affiliation: Program in Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: Siyi
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Program in Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Ball
authors.affiliation: Program in Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Rikesh
authors.initials: R
authors.lastname: Gandhi
authors.affiliation: Program in Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: Hongrui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Program in Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Program in Developmental and Stem Cell Biology, Research Institute, The Hospital for Sick Children, Department of Immunology, University of Toronto, Toronto, Canada.
authors.forename: Julie S
authors.initials: JS
authors.lastname: Yuan
authors.affiliation: Program in Developmental and Stem Cell Biology, Research Institute, The Hospital for Sick Children, Department of Immunology, University of Toronto, Toronto, Canada.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Guidos
authors.affiliation: Program in Physiology & Experimental Medicine, Research Institute, Division of Gastroenterology & Nutrition, The Hospital for Sick Children, Department of Paediatrics, University of Toronto, Toronto, Canada.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Durie
authors.affiliation: Program in Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Rommens
mesh_terms: D061354:Acinar Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D001855:Bone Marrow Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D016922:Cellular Senescence; D010188:Exocrine Pancreatic Insufficiency / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008068:Lipomatosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism*; D000081003:Shwachman-Diamond Syndrome; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D011506:Proteins; C513661:Sbds protein, mouse; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53