title: Early pancreatic islet fate and maturation is controlled through RBP-Jκ.
abstract: Notch signaling is known to control early pancreatic differentiation through Ngn3 repression. In later stages, downstream of Notch, the Presenilins are still required to maintain the endocrine fate allocation. Amongst their multiple targets, it remains unclear which one actually controls the maintenance of the fate of the early islets. Conditional deletions of the Notch effector RBP-Jκ with lineage tracing in Presenilin-deficient endocrine progenitors, demonstrated that this factor is central to the control of the fate through a non-canonical Notch mechanism. RBP-Jκ mice exhibit normal islet morphogenesis and function, however, a fraction of the progenitors fails to differentiate and develop into disorganized masses resembling acinar to ductal metaplasia and chronic pancreatitis. A subsequent deletion of RBP-Jκ in forming β-cells led to the transdifferentiation into the other endocrine cells types, indicating that this factor still mediates the maintenance of the fate within the endocrine lineage itself. These results highlight the dual importance of Notch signaling for the endocrine lineage. Even after Ngn3 expression, Notch activity is required to maintain both fate and maturation of the Ngn3 progenitors. In a subset of the cells, these alterations of Notch signaling halt their differentiation and leads to acinar to ductal metaplasia.
authors.affiliation: University of Michigan in Ann Arbor, Internal Medicine Department, MEND Division Brehm Tower, 1000 Wall St, Ann Arbor, MI 48105-1912, USA.
authors.forename: Corentin
authors.initials: C
authors.lastname: Cras-Méneur
authors.affiliation: University of Michigan in Ann Arbor, Internal Medicine Department, MEND Division Brehm Tower, 1000 Wall St, Ann Arbor, MI 48105-1912, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Conlon
authors.affiliation: University of Michigan in Ann Arbor, Department of Surgery, General Surgery Division 4304 Cancer Center, 1500 E. Medical Center Drive, Ann Arbor MI 48109-5936, USA.
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: University of Michigan in Ann Arbor, Department of Surgery, General Surgery Division 4304 Cancer Center, 1500 E. Medical Center Drive, Ann Arbor MI 48109-5936, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Pasca Di Magliano
authors.affiliation: University of Miami Miller School of Medicine, Department of General Internal Medicine, Division of Endocrinology, Diabetes and Metabolism 1400 NW 10th Ave, Miami, FL 33136-1031, USA.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Bernal-Mizrachi
mesh_terms: D061354:Acinar Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics; D004622:Embryo, Mammalian; D019858:Enteroendocrine Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000172:deficiency / Q000235:genetics*; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008679:Metaplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis / Q000235:genetics*; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D053764:Presenilin-1 / Q000172:deficiency / Q000235:genetics; D053766:Presenilin-2 / Q000172:deficiency / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001426:Bacterial Proteins; D051792:Basic Helix-Loop-Helix Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D019426:Integrases; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D053764:Presenilin-1; D053766:Presenilin-2; D051880:Receptors, Notch; C407737:Neurog3 protein, mouse; C095101:Psen2 protein, mouse; C580804:presenilin 1, mouse; C054562:yellow fluorescent protein, Bacteria; C045073:Cre recombinase