title: Perturbations to the IGF1 growth pathway and adult energy homeostasis following disruption of mouse chromosome 12 imprinting.
abstract: OBJECTIVE
  Disruption to insulin-like growth factor (IGF) signalling pathways during early life causes growth retardation and defects of developing metabolic organs that can alter set points of energy homeostasis for a lifetime. Inheritance of two maternal copies of human chromosome 14q32.2 (Temple syndrome) causes severe foetal growth retardation and post-natal failure to thrive. Disruption of imprinted gene dosage in the orthologous region on mouse chromosome 12 also affects growth. Here, we investigated whether altering chromosome 12-imprinted gene dosage can affect IGF signalling.
  
  
  METHODS
  We investigated mice with a transgene insertion at the imprinted domain of chromosome 12. This lesion causes misexpression of neighbouring genes such that the expression of non-coding RNAs is elevated, and levels of delta-like homologue 1 (Dlk1), retrotransposon-like 1 (Rtl1) and deiodinase 3 (Dio3) transcripts are reduced.
  
  
  RESULTS
  We observed three key phenotypes in these mice: (i) embryonic growth retardation associated with altered expression of IGF1 binding proteins, (ii) peri-natal failure to thrive accompanied by hypothyroidism and low serum IGF1. Unexpectedly this phenotype was growth hormone independent. (iii) Adult animals had reduced glucose tolerance as a result of endocrine pancreatic insufficiency.
  
  
  CONCLUSIONS
  We propose that all of these phenotypes are attributable to impaired IGF action and show for the first time that the chromosome 12 cluster in the mouse is an imprinted locus that modulates the IGF signalling pathway. We propose that growth retardation observed in human Temple syndrome might have a similar cause.
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
authors.forename: M
authors.initials: M
authors.lastname: Charalambous
authors.forename: S T
authors.initials: ST
authors.lastname: da Rocha
authors.forename: A
authors.initials: A
authors.lastname: Hernandez
authors.forename: A C
authors.initials: AC
authors.lastname: Ferguson-Smith
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D033481:Chromosomes, Mammalian / Q000235:genetics*; D004734:Energy Metabolism / Q000235:genetics*; D010188:Exocrine Pancreatic Insufficiency / Q000235:genetics*; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics*; D018392:Genomic Imprinting / Q000235:genetics*; D005947:Glucose / Q000235:genetics; D006706:Homeostasis / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D005947:Glucose
keywords: IGF1 signalling; growth; imprinting
references.citation: J Endocrinol. 1996 Aug;150(2):231-42
references.pmid: 8869590
references.citation: Endocrinology. 1988 Dec;123(6):2827-33
references.pmid: 3197646
references.citation: Nat Genet. 2003 Sep;35(1):97-102
references.pmid: 12937418
references.citation: Development. 1992 Mar;114(3):711-20
references.pmid: 1618138
references.citation: Cytogenet Genome Res. 2006;113(1-4):223-9
references.pmid: 16575184
references.citation: Curr Opin Endocrinol Diabetes Obes. 2007 Feb;14(1):3-12
references.pmid: 17940412
references.citation: Epigenetics. 2008 Jul-Aug;3(4):181-7
references.pmid: 18698157
references.citation: BMC Genet. 2006 Oct 03;7:44
references.pmid: 17014736
references.citation: Nature. 1991 Jun 20;351(6328):667-70
references.pmid: 2052093
references.citation: Cell Metab. 2012 Feb 8;15(2):209-21
references.pmid: 22326222
references.citation: J Endocrinol. 2001 Oct;171(1):15-22
references.pmid: 11572786
references.citation: Curr Biol. 2000 Sep 21;10(18):1135-8
references.pmid: 10996796
references.citation: Nature. 1991 Jan 3;349(6304):84-7
references.pmid: 1845916
references.citation: J Biol Chem. 2000 May 26;275(21):16258-66
references.pmid: 10748196
references.citation: Endocrinology. 2007 Dec;148(12):5680-7
references.pmid: 17823249
references.citation: EMBO J. 2003 Jun 16;22(12):3039-49
references.pmid: 12805218
references.citation: Endocrinology. 2011 Oct;152(10):3717-27
references.pmid: 21828183
references.citation: Nature. 1998 May 14;393(6681):125-6
references.pmid: 9603515
references.citation: Genome Res. 2001 Dec;11(12):2085-94
references.pmid: 11731499
references.citation: Genes Dev. 1999 May 15;13(10):1329-41
references.pmid: 10346821
references.citation: PLoS Genet. 2009 Feb;5(2):e1000392
references.pmid: 19247431
references.citation: Nat Genet. 2002 May;31(1):111-5
references.pmid: 11923875
references.citation: PLoS Genet. 2012;8(4):e1002605
references.pmid: 22511876
references.citation: Endocrinology. 2006 Oct;147(10):4730-7
references.pmid: 16809446
references.citation: Mol Endocrinol. 2006 Sep;20(9):2173-86
references.pmid: 16675541
references.citation: J Endocrinol. 1997 Jul;154(1):155-65
references.pmid: 9246950
references.citation: Hum Mol Genet. 2002 Jan 1;11(1):77-86
references.pmid: 11773001
references.citation: Am J Med Genet C Semin Med Genet. 2010 Aug 15;154C(3):329-34
references.pmid: 20803655
references.citation: Cancer Res. 1996 Jul 15;56(14):3165-7
references.pmid: 8764099
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8292-7
references.pmid: 12829789
references.citation: Trends Genet. 2008 Jun;24(6):306-16
references.pmid: 18471925
references.citation: Nature. 1995 May 4;375(6526):34-9
references.pmid: 7536897
references.citation: J Cell Biochem. 2010 Sep 1;111(1):14-9
references.pmid: 20506515
references.citation: Nature. 1990 May 3;345(6270):78-80
references.pmid: 2330056
references.citation: J Endocrinol. 1991 Jun;129(3):459-64
references.pmid: 2066700
references.citation: Development. 2000 Nov;127(21):4719-28
references.pmid: 11023874
references.citation: Nat Genet. 2008 Feb;40(2):243-8
references.pmid: 18176565
references.citation: Nat Genet. 1999 Sep;23(1):32-40
references.pmid: 10471495
references.citation: Trends Endocrinol Metab. 2008 Aug;19(6):197-205
references.pmid: 18515143
references.citation: Dev Biol. 2001 Jan 1;229(1):141-62
references.pmid: 11133160
references.citation: Mamm Genome. 1996 Jan;7(1):20-4
references.pmid: 8903723
references.citation: Nature. 1997 Oct 23;389(6653):809-15
references.pmid: 9349812
references.citation: Cell. 1991 Feb 22;64(4):849-59
references.pmid: 1997210
references.citation: J Clin Invest. 2006 Feb;116(2):476-84
references.pmid: 16410833
references.citation: Nat Cell Biol. 2012 Jun 10;14(7):659-65
references.pmid: 22684254
references.citation: Diabetologia. 1993 Jan;36(1):62-7
references.pmid: 8436255
references.citation: Dev Biol. 2010 Jan 1;337(1):1-8
references.pmid: 19833122
references.citation: Hum Genet. 2007 Aug;122(1):1-21
references.pmid: 17534663
references.citation: Int J Dev Biol. 1998;42(7):955-76
references.pmid: 9853827
references.citation: J Endocrinol. 2010 Aug;206(2):195-204
references.pmid: 20488945
references.citation: EMBO J. 1997 Jul 16;16(14):4412-20
references.pmid: 9250685
references.citation: Mol Cell Biol. 2002 Aug;22(15):5585-92
references.pmid: 12101250
references.citation: Mamm Genome. 2003 Aug;14(8):495-505
references.pmid: 12925882
references.citation: Best Pract Res Clin Endocrinol Metab. 2011 Feb;25(1):77-100
references.pmid: 21396576
references.citation: Mol Genet Metab. 2005 Sep-Oct;86(1-2):84-90
references.pmid: 16165387