title: Loss of Fbw7 reprograms adult pancreatic ductal cells into α, δ, and β cells.
abstract: The adult pancreas is capable of limited regeneration after injury but has no defined stem cell population. The cell types and molecular signals that govern the production of new pancreatic tissue are not well understood. Here, we show that inactivation of the SCF-type E3 ubiquitin ligase substrate recognition component Fbw7 induces pancreatic ductal cells to reprogram into α, δ, and β cells. Loss of Fbw7 stabilized the transcription factor Ngn3, a key regulator of endocrine cell differentiation. The induced β cells resemble islet β cells in morphology and histology, express genes essential for β cell function, and release insulin after glucose challenge. Thus, loss of Fbw7 appears to reawaken an endocrine developmental differentiation program in adult pancreatic ductal cells. Our study highlights the plasticity of seemingly differentiated adult cells, identifies Fbw7 as a master regulator of cell fate decisions in the pancreas, and reveals adult pancreatic duct cells as a latent multipotent cell type.
authors.affiliation: Mammalian Genetics Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Rocio
authors.initials: R
authors.lastname: Sancho
authors.affiliation: Mammalian Genetics Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Ralph
authors.initials: R
authors.lastname: Gruber
authors.affiliation: Department of Cell and Developmental Biology, School of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Gu
authors.affiliation: Mammalian Genetics Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44, Lincoln's Inn Fields, London WC2A 3LY, UK; School of Medicine, King's College London, Guy's Campus, London SE1 1UL, UK. Electronic address: axel.behrens@cancer.org.uk.
authors.forename: Axel
authors.initials: A
authors.lastname: Behrens
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019070:Cell Lineage; D044783:F-Box Proteins / Q000235:genetics / Q000502:physiology*; D000073979:F-Box-WD Repeat-Containing Protein 7; D017353:Gene Deletion; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D050416:Glucagon-Secreting Cells / Q000166:cytology*; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology*; D051379:Mice; D039902:Multipotent Stem Cells / Q000166:cytology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D010183:Pancreatic Ducts / Q000166:cytology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012038:Regeneration / Q000235:genetics; D019864:Somatostatin-Secreting Cells / Q000166:cytology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*; D054875:Ubiquitination
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D005947:Glucose; D007328:Insulin; D009419:Nerve Tissue Proteins; D046988:Proteasome Endopeptidase Complex; D044767:Ubiquitin-Protein Ligases; C513272:Fbxw7 protein, mouse; C407737:Neurog3 protein, mouse
references.citation: Dev Biol. 1992 Oct;153(2):368-75
references.pmid: 1356859
references.citation: Cell Death Dis. 2013 Mar 07;4:e523
references.pmid: 23470530
references.citation: Gastroenterology. 2010 Sep;139(3):929-41
references.pmid: 20638938
references.citation: Gastroenterology. 2011 Oct;141(4):1451-62, 1462.e1-6
references.pmid: 21763240
references.citation: Nat Neurosci. 2010 Nov;13(11):1365-72
references.pmid: 20935640
references.citation: Nat Cell Biol. 2010 Oct;12(10):963-72
references.pmid: 20852630
references.citation: Nat Rev Genet. 2002 Jul;3(7):524-32
references.pmid: 12094230
references.citation: Nat Genet. 2000 Jan;24(1):36-44
references.pmid: 10615124
references.citation: J Endocrinol. 2004 Apr;181(1):11-23
references.pmid: 15072563
references.citation: Genes Dev. 2008 Aug 1;22(15):1998-2021
references.pmid: 18676806
references.citation: Cell Death Differ. 2006 Nov;13(11):1892-9
references.pmid: 16514419
references.citation: Biochem Soc Trans. 2008 Jun;36(Pt 3):353-6
references.pmid: 18481956
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):14920-5
references.pmid: 14657333
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19915-9
references.pmid: 19052237
references.citation: Nature. 2007 Feb 8;445(7128):661-5
references.pmid: 17251932
references.citation: Nature. 1999 Aug 26;400(6747):877-81
references.pmid: 10476967
references.citation: PLoS One. 2012;7(5):e37055
references.pmid: 22606327
references.citation: Nat Rev Cancer. 2006 May;6(5):369-81
references.pmid: 16633365
references.citation: Pediatr Diabetes. 2004;5 Suppl 2:16-22
references.pmid: 15601370
references.citation: Oncogene. 2008 Oct 16;27(47):6164-74
references.pmid: 18641686
references.citation: Stem Cells Transl Med. 2012 Feb;1(2):150-9
references.pmid: 23197762
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9085-90
references.pmid: 15150404
references.citation: Cell. 2013 May 9;153(4):747-58
references.pmid: 23623304
references.citation: Nat Rev Genet. 2008 May;9(5):329-40
references.pmid: 18398419
references.citation: Biol Open. 2012 Dec 15;1(12):1264-72
references.pmid: 23259061
references.citation: J Exp Med. 2007 Nov 26;204(12):2875-88
references.pmid: 17984302
references.citation: Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15336-41
references.pmid: 22949652
references.citation: Diabetes. 2011 May;60(5):1370-9
references.pmid: 21525508
references.citation: Development. 2013 Jun;140(12):2472-83
references.pmid: 23715541
references.citation: Endocrinology. 2005 Mar;146(3):1025-34
references.pmid: 15604203
references.citation: Am J Physiol Endocrinol Metab. 2003 Jan;284(1):E177-83
references.pmid: 12388130
references.citation: Cell. 2008 Jan 25;132(2):197-207
references.pmid: 18243096
references.citation: Dev Biol. 2011 Oct 1;358(1):201-12
references.pmid: 21827743
references.citation: Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1607-11
references.pmid: 10677506
references.citation: Development. 2004 Sep;131(17):4213-24
references.pmid: 15280211
references.citation: J Clin Invest. 2011 Jan;121(1):342-54
references.pmid: 21123947
references.citation: J Biol Chem. 2013 Apr 26;288(17):11705-17
references.pmid: 23471965
references.citation: Dev Cell. 2013 Jul 15;26(1):86-100
references.pmid: 23810513
references.citation: Development. 1995 Oct;121(10):3291-301
references.pmid: 7588063
references.citation: J Biol Chem. 2011 Apr 15;286(15):13754-64
references.pmid: 21349854
references.citation: J Exp Med. 2008 Jun 9;205(6):1395-408
references.pmid: 18474632
references.citation: Nature. 2005 Sep 8;437(7056):281-5
references.pmid: 16007074
references.citation: Nat Rev Cancer. 2008 Feb;8(2):83-93
references.pmid: 18094723
references.citation: Nat Biotechnol. 2014 Jan;32(1):76-83
references.pmid: 24240391
references.citation: BMC Dev Biol. 2001;1:4
references.pmid: 11299042
references.citation: Diabetes. 2005 Sep;54(9):2557-67
references.pmid: 16123343
references.citation: Blood. 2011 Feb 24;117(8):2373-7
references.pmid: 21190997
references.citation: Genesis. 2008 Jun;46(6):318-23
references.pmid: 18543299
references.citation: Cell. 2009 Aug 7;138(3):449-62
references.pmid: 19665969
references.citation: Nat Cell Biol. 2007 Jul;9(7):765-74
references.pmid: 17558397
references.citation: Dev Biol. 2008 May 15;317(2):531-40
references.pmid: 18394599
references.citation: Cell Metab. 2006 Jan;3(1):59-65
references.pmid: 16399505
references.citation: Nature. 2008 Oct 2;455(7213):627-32
references.pmid: 18754011
references.citation: Nature. 2004 May 6;429(6987):41-6
references.pmid: 15129273
references.citation: EMBO Rep. 2011 Dec 23;13(1):36-43
references.pmid: 22157894
references.citation: J Cell Biol. 2008 Jun 16;181(6):913-20
references.pmid: 18559665
references.citation: Cancer Cell. 2003 Dec;4(6):437-50
references.pmid: 14706336
references.citation: J Cell Biol. 2002 Oct 28;159(2):303-12
references.pmid: 12403815
references.citation: PLoS Biol. 2013;11(6):e1001586
references.pmid: 23776410
references.citation: Development. 2000 Aug;127(16):3533-42
references.pmid: 10903178
references.citation: Nucleic Acids Res. 2009 Apr;37(7):e55
references.pmid: 19279185