Premature ovarian failure in mice with oocytes lacking core 1-derived O-glycans and complex N-glycans.
Premature ovarian failure (POF) affects up to 1.4% of women under the age of 40 yr and less than 30% of cases have a known cause. Here we describe a new mouse model of POF resulting from oocyte-specific ablation of core 1-derived (mucin) O-glycans and complex and hybrid N-glycans. Females carrying floxed alleles of both the C1galt1 (T-syn) and Mgat1 glycosyltransferase genes and a ZP3Cre transgene, generate oocytes lacking complex O- and N-glycans following oocyte-specific deletion at the primary follicle stage. We previously showed that few double-mutant females are fertile, and those produce only a single small litter. Here we show that ovarian function declined rapidly in double-mutant females with less than 1% ovulating at 11 wk of age after superovulation with exogenous gonadotropins. Ovary weight was significantly decreased in double-mutant females by 3 months of age, consistent with a decrease in the number of developing follicles. FSH levels in double-mutant females were elevated at 3 months of age, and testosterone and inhibin A were decreased, showing that the loss of complex N- and O-glycans from oocyte glycoproteins affected hypothalamic-pituitary-gonadal feedback loops. The absence of developing follicles, ovary dysfunction, reduced testosterone and inhibin A, and elevated FSH in double-mutant females lacking C1galt1 and Mgat1 in oocytes represents a new mouse model for the study of follicular POF.
Department of Cell Biology, Albert Einstein College of Medicine, New York, New York 10461, USA. suzannah.williams@dpag.ox.ac.uk
Suzannah A
SA
Williams
Pamela
P
Stanley
D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004527:Egg Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005700:Galactosyltransferases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D009077:Mucins; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases; D009865:Oocytes / Q000502:physiology*; D011134:Polysaccharides / Q000737:chemistry* / Q000378:metabolism*; D016649:Primary Ovarian Insufficiency / Q000378:metabolism*; D011374:Progesterone / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D013480:Superovulation; D000072216:Zona Pellucida Glycoproteins
D004527:Egg Proteins; D008562:Membrane Glycoproteins; D009077:Mucins; D011134:Polysaccharides; D011956:Receptors, Cell Surface; D000072216:Zona Pellucida Glycoproteins; D011374:Progesterone; D000217:Acyltransferases; C515597:C1galt1 protein, mouse; D005700:Galactosyltransferases; C459903:MGAT1 protein, mouse; D017351:N-Acetylglucosaminyltransferases
J Obstet Gynaecol. 2007 Jan;27(1):16-9
17365451
J Cell Biol. 2004 Feb 2;164(3):451-9
14745002
Curr Biol. 1997 Feb 1;7(2):148-51
9016703
Orphanet J Rare Dis. 2006 Apr 06;1:9
16722528
Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):728-32
8290590
Mol Cell Endocrinol. 2010 Feb 5;315(1-2):1-10
19643165
Sex Dev. 2008;2(4-5):228-43
18987497
Endocrinology. 1999 Nov;140(11):5202-10
10537150
Menopause Int. 2009 Jun;15(2):72-5
19465673
Curr Opin Obstet Gynecol. 2006 Aug;18(4):418-26
16794423
Hum Mol Genet. 2009 Aug 1;18(15):2813-24
19423553
Gynecol Endocrinol. 2008 Jan;24(1):44-53
18224544
Biol Reprod. 1993 Nov;49(5):895-907
8286585
Endocrinology. 2009 Feb;150(2):1014-24
18818300
Hum Reprod. 2003 Jan;18(1):199-206
12525467
FASEB J. 2008 Jul;22(7):2273-84
18276833
Biol Reprod. 1971 Apr;4(2):154-60
5115002
Mol Endocrinol. 1999 Jun;13(6):1018-34
10379899
J Med Genet. 2009 Jul;46(7):455-7
19429596
Dev Biol. 1987 Jun;121(2):568-75
2884155
Hum Reprod. 2004 Nov;19(11):2555-60
15319385
Glycobiology. 2003 Jan;13(1):43-50
12634323
Menopause. 2008 Jan-Feb;15(1):23-31
18257141
Hum Reprod Update. 2010 Mar-Apr;16(2):177-88
19793842
J Biomed Mater Res A. 2004 Jan 1;68(1):168-76
14661262
J Biol Chem. 2002 Jan 4;277(1):169-77
11673471
EMBO J. 1994 May 1;13(9):2056-65
8187759
Nat Genet. 2000 Jul;25(3):279-83
10888873
Mol Cell Biol. 2004 Nov;24(22):9920-9
15509794
J Biol Chem. 2001 Apr 6;276(14):11387-92
11154695
J Biol Chem. 2002 Jan 4;277(1):178-86
11677243
Science. 2008 Feb 1;319(5863):611-3
18239123
Biol Reprod. 2000 Jun;62(6):1467-78
10819746
Obstet Gynecol. 1986 Apr;67(4):604-6
3960433
J Cell Sci. 2007 Apr 15;120(Pt 8):1341-9
17374637
Reproduction. 2002 Jan;123(1):23-30
11869183
Endocr Rev. 1997 Feb;18(1):107-34
9034788
Biomaterials. 2007 Oct;28(30):4439-48
17643486
J Reprod Fertil. 1968 Dec;17(3):555-7
5715685
Mol Endocrinol. 2006 Jun;20(6):1406-22
16513794
Adv Exp Med Biol. 2005;564:99-100
16400812
Reproduction. 2009 Feb;137(2):321-31
19028923
Nature. 1996 Oct 10;383(6600):531-5
8849725
Fertil Steril. 1992 Jan;57(1):56-61
1730331
Endocrinology. 2000 Nov;141(11):4284-94
11089564
J Biol Chem. 2002 Nov 8;277(45):42795-801
12205101
Endocrinology. 1970 Aug;87(2):286-93
5424997
J Biol Chem. 2000 Mar 17;275(11):7731-42
10713085
Biol Reprod. 2000 Feb;62(2):370-7
10642575