title: Loss of glycogen synthase kinase 3 isoforms during murine oocyte growth induces offspring cardiac dysfunction.
abstract: Glycogen synthase kinase-3 (GSK3) is a constitutively active serine threonine kinase with 1) two isoforms (GSK3A and GSK3B) that have unique and overlapping functions, 2) multiple molecular intracellular mechanisms that involve phosphorylation of diverse substrates, and 3) implications in pathogenesis of many diseases. Insulin causes phosphorylation and inactivation of GSK3 and mammalian oocytes have a functional insulin-signaling pathway whereby prolonged elevated insulin during follicle/oocyte development causes GSK3 hyperphosphorylation, reduced GSK3 activity, and altered oocyte chromatin remodeling. Periconceptional diabetes and chronic hyperinsulinemia are associated with congenital malformations and onset of adult diseases of cardiovascular origin. Objectives were to produce transgenic mice with individual or concomitant loss of GSK3A and/or GSK3B and investigate the in vivo role of oocyte GSK3 on fertility, fetal development, and offspring health. Wild-type males bred to females with individual or concomitant loss of oocyte GSK3 isoforms did not have reduced fertility. However, concomitant loss of GSK3A and GSK3B in the oocyte significantly increased neonatal death rate due to congestive heart failure secondary to ventricular hyperplasia. Individual loss of oocyte GSK3A or GSK3B did not induce this lethal phenotype. In conclusion, absence of oocyte GSK3 in the periconceptional period does not alter fertility yet causes offspring cardiac hyperplasia, cardiovascular defects, and significant neonatal death. These results support a developmental mechanism by which periconceptional hyperinsulinemia associated with maternal metabolic syndrome, obesity, and/or diabetes can act on the oocyte and affect offspring cardiovascular development, function, and congenital heart malformation.
authors.affiliation: Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan.
authors.forename: André
authors.initials: A
authors.lastname: Monteiro da Rocha
authors.affiliation: Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Jun
authors.initials: J
authors.lastname: Ding
authors.affiliation: Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Nicole
authors.initials: N
authors.lastname: Slawny
authors.affiliation: Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Amber M
authors.initials: AM
authors.lastname: Wolf
authors.affiliation: Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan Department of Urology, University of Michigan, Ann Arbor, Michigan Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan smithgd@umich.edu.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Smith
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006331:Heart Diseases / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010375:Pedigree
chemical_list: D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha
keywords: congenital heart malformation; glycogen synthase kinase 3; mouse gene knockout; oocyte; periconception
references.citation: Semin Reprod Endocrinol. 1999;17(2):127-36
references.pmid: 10528364
references.citation: J Endocrinol. 1999 Nov;163(2):363-72
references.pmid: 10556787
references.citation: Nature. 2000 Jul 6;406(6791):86-90
references.pmid: 10894547
references.citation: Biotechniques. 2000 Jul;29(1):52, 54
references.pmid: 10907076
references.citation: Eur J Biochem. 2000 Oct;267(19):5983-94
references.pmid: 10998059
references.citation: Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):11960-5
references.pmid: 11035810
references.citation: Cell. 2000 Oct 13;103(2):185-8
references.pmid: 11057891
references.citation: Early Hum Dev. 2001 Mar;61(2):85-95
references.pmid: 11223271
references.citation: EMBO J. 2002 Feb 1;21(3):281-93
references.pmid: 11823421
references.citation: Mol Reprod Dev. 2003 Jan;64(1):96-105
references.pmid: 12420304
references.citation: Mol Reprod Dev. 1992 Feb;31(2):87-95
references.pmid: 1318055
references.citation: Biol Reprod. 2004 Nov;71(5):1469-74
references.pmid: 15215191
references.citation: Mol Reprod Dev. 2007 Feb;74(2):178-88
references.pmid: 16941690
references.citation: Diabetologia. 2007 Feb;50(2):452-60
references.pmid: 17151860
references.citation: Biol Reprod. 2007 Apr;76(4):628-38
references.pmid: 17182892
references.citation: Diabetes Res Clin Pract. 2007 Sep;77 Suppl 1:S49-57
references.pmid: 17478001
references.citation: Dev Cell. 2007 Jun;12(6):957-71
references.pmid: 17543867
references.citation: Dev Cell. 2007 Jul;13(1):10-3
references.pmid: 17609106
references.citation: Biol Reprod. 2007 Nov;77(5):872-9
references.pmid: 17625112
references.citation: Cell Signal. 2007 Nov;19(11):2255-63
references.pmid: 17716861
references.citation: Cell Metab. 2007 Oct;6(4):329-37
references.pmid: 17908561
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 29;105(4):1333-8
references.pmid: 18212115
references.citation: Diabetologia. 2008 Apr;51(4):623-31
references.pmid: 18219478
references.citation: PLoS Biol. 2008 Feb;6(2):e37
references.pmid: 18288891
references.citation: Biochem J. 1991 Feb 1;273 ( Pt 3):673-8
references.pmid: 1847619
references.citation: J Clin Invest. 2008 Nov;118(11):3609-18
references.pmid: 18830417
references.citation: Birth Defects Res A Clin Mol Teratol. 2009 Jun;85(6):523-30
references.pmid: 19180650
references.citation: Cell. 2009 Mar 20;136(6):1017-31
references.pmid: 19303846
references.citation: Reproduction. 2009 Aug;138(2):235-46
references.pmid: 19470708
references.citation: Biochim Biophys Acta. 2010 Mar;1804(3):598-603
references.pmid: 19770076
references.citation: Am J Obstet Gynecol. 2010 Jan;202(1):51.e1-51.e10
references.pmid: 19796755
references.citation: J Clin Invest. 2010 Jul;120(7):2280-91
references.pmid: 20516643
references.citation: Am J Obstet Gynecol. 2010 Dec;203(6):525-30
references.pmid: 20739012
references.citation: PLoS One. 2010 Aug 25;5(8):e12418
references.pmid: 20811634
references.citation: Diabetologia. 2010 Dec;53(12):2600-10
references.pmid: 20821187
references.citation: J Neurochem. 2010 Nov;115(4):974-83
references.pmid: 20831597
references.citation: J Biol Chem. 2010 Dec 31;285(53):41337-47
references.pmid: 21047779
references.citation: Endocrinology. 2011 May;152(5):1755-66
references.pmid: 21325041
references.citation: Results Probl Cell Differ. 2011;53:309-41
references.pmid: 21630151
references.citation: EMBO J. 1990 Aug;9(8):2431-8
references.pmid: 2164470
references.citation: Curr Diab Rep. 2012 Feb;12(1):24-32
references.pmid: 22167469
references.citation: PLoS One. 2012;7(4):e35538
references.pmid: 22514749
references.citation: Cell Prolif. 2012 Aug;45(4):287-98
references.pmid: 22571232
references.citation: J Biol Chem. 2012 Aug 24;287(35):29227-36
references.pmid: 22761446
references.citation: Philos Trans R Soc Lond B Biol Sci. 2012 Sep 5;367(1601):2460-74
references.pmid: 22826345
references.citation: Cardiovasc Res. 2012 Dec 1;96(3):352-62
references.pmid: 22893679
references.citation: Biochim Biophys Acta. 2013 Mar;1830(3):2574-82
references.pmid: 23274741
references.citation: Nat Struct Mol Biol. 2013 Mar;20(3):311-6
references.pmid: 23416945
references.citation: Mol Reprod Dev. 2013 Apr;80(4):286-96
references.pmid: 23426897
references.citation: Mol Hum Reprod. 2013 Jul;19(7):415-22
references.pmid: 23515667
references.citation: PLoS Genet. 2013 Apr;9(4):e1003439
references.pmid: 23637617
references.citation: Mol Brain. 2013 May 25;6:27
references.pmid: 23705847
references.citation: Carcinogenesis. 2013 Oct;34(10):2206-17
references.pmid: 23715499
references.citation: Hum Reprod Update. 2013 Nov-Dec;19(6):640-55
references.pmid: 23959022
references.citation: Dev Cell. 2013 Oct 28;27(2):227-240
references.pmid: 24120884
references.citation: Lancet. 1986 May 10;1(8489):1077-81
references.pmid: 2871345
references.citation: EMBO J. 1986 Jan;5(1):157-60
references.pmid: 3514207
references.citation: Science. 1979 Sep 28;205(4413):1397-9
references.pmid: 472755
references.citation: Eur J Biochem. 1980 Jun;107(2):529-37
references.pmid: 6772446
references.citation: Teratology. 1982 Jun;25(3):385-94
references.pmid: 7051398
references.citation: J Reprod Fertil. 1994 Mar;100(2):375-80
references.pmid: 7517453
references.citation: FEBS Lett. 1993 Jul 5;325(3):167-72
references.pmid: 7686508
references.citation: Biochem J. 1994 Oct 1;303 ( Pt 1):21-6
references.pmid: 7945242
references.citation: Eur J Pediatr. 1994 Aug;153(8):574-80
references.pmid: 7957404
references.citation: Genes Dev. 1994 Dec 15;8(24):2953-63
references.pmid: 8001817
references.citation: Nature. 1993 Apr 22;362(6422):749-51
references.pmid: 8097018
references.citation: Biochem J. 1993 Nov 15;296 ( Pt 1):15-9
references.pmid: 8250835
references.citation: Biochem J. 1993 Sep 15;294 ( Pt 3):625-9
references.pmid: 8397507
references.citation: Nature. 1995 Dec 21-28;378(6559):785-9
references.pmid: 8524413
references.citation: Neurosci Lett. 1995 Sep 8;197(2):149-53
references.pmid: 8552282
references.citation: Science. 1996 May 17;272(5264):1023-6
references.pmid: 8638126
references.citation: Mol Cell Biol. 1996 Jun;16(6):2857-64
references.pmid: 8649395
references.citation: Curr Biol. 1997 Apr 1;7(4):261-9
references.pmid: 9094314
references.citation: Mol Reprod Dev. 1997 Jun;47(2):134-9
references.pmid: 9136113
references.citation: Am J Perinatol. 1997 Feb;14(2):59-62
references.pmid: 9259899
references.citation: Curr Biol. 1998 May 7;8(10):573-81
references.pmid: 9601641