title: Dysregulation of follicle development in a mouse model of premature ovarian insufficiency.
abstract: Premature ovarian insufficiency (POI) occurs in 1% of reproductive-age women. The ovarian manifestation ranges from the presence of a variable population of follicles (follicular) to the absence of follicles (afollicular), and in the majority of cases the cause is unknown. A transgenic mouse model of follicular POI, the Double Mutant (DM), arises from oocyte-specific deletion of Mgat1 and C1galt1 required for the generation of O- and N-glycans. DM females are subfertile at 6 weeks, infertile by 9 weeks and exhibit POI by 12 weeks of age. In this study we investigate the cause of the reduced fertility at 6 weeks and infertility at 9 weeks of DM females. Ovary sections were used to analyse follicle and corpora lutea (CL) numbers, apoptosis, and levels of laminin and 3β-hydroxysteroid dehydrogenase using immunohistochemistry. After POI, DM females unexpectedly remained sexually receptive. At both 6 and 9 weeks, DM ovaries contained more primary follicles, however, at 9 weeks DM follicles were proportionally healthier, revealed by TUNEL analysis compared with Controls. In 9 week DM ovaries (collected post-mating), secondary follicles had theca and basal lamina structure abnormalities, whilst preovulatory follicles failed to ovulate resulting in the presence of numerous luteinised unruptured follicles, indicative of ovulation failure. Finally, DM ovaries contained more regressing CL with decreased luteal cell apoptosis indicative of a defect in CL regression. Identifying these follicular modifications have provided insight into the aetiology of a model of POI and highlight targets to investigate with the hope of developing new fertility treatments.
authors: Nuffield Department of Obstetrics and GynaecologyUniversity of Oxford, Women's Centre, Level 3, John Radcliffe Hospital, Oxford, UK.
authors: P
authors: P
authors: Grasa
authors: Nuffield Department of Obstetrics and GynaecologyUniversity of Oxford, Women's Centre, Level 3, John Radcliffe Hospital, Oxford, UK.
authors: S
authors: S
authors: Sheikh
authors: Nuffield Department of Obstetrics and GynaecologyUniversity of Oxford, Women's Centre, Level 3, John Radcliffe Hospital, Oxford, UK Department of PhysiologyAnatomy and Genetics, University of Oxford, Oxford, UK.
authors: N
authors: N
authors: Krzys
authors: Nuffield Department of Obstetrics and GynaecologyUniversity of Oxford, Women's Centre, Level 3, John Radcliffe Hospital, Oxford, UK.
authors: K
authors: K
authors: Millar
authors: Nuffield Department of Obstetrics and GynaecologyUniversity of Oxford, Women's Centre, Level 3, John Radcliffe Hospital, Oxford, UK Department of PhysiologyAnatomy and Genetics, University of Oxford, Oxford, UK.
authors: S
authors: S
authors: Janjua
authors: Nuffield Department of Obstetrics and GynaecologyUniversity of Oxford, Women's Centre, Level 3, John Radcliffe Hospital, Oxford, UK.
authors: P
authors: P
authors: Nawaggi
authors: Nuffield Department of Obstetrics and GynaecologyUniversity of Oxford, Women's Centre, Level 3, John Radcliffe Hospital, Oxford, UK suzannah.williams@obs-gyn.ox.ac.uk.
authors: S A
authors: SA
authors: Williams
mesh_terms: D000217:Acyltransferases / Q000502:physiology*; D000818:Animals; D005260:Female; D005298:Fertility; D005700:Galactosyltransferases / Q000502:physiology*; D019426:Integrases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases; D009865:Oocytes / Q000378:metabolism / Q000473:pathology*; D006080:Ovarian Follicle / Q000378:metabolism / Q000473:pathology*; D010060:Ovulation / Q000235:genetics; D016649:Primary Ovarian Insufficiency / Q000209:etiology / Q000473:pathology*
chemical_list: D000217:Acyltransferases; C515597:C1galt1 protein, mouse; D005700:Galactosyltransferases; C459903:MGAT1 protein, mouse; D017351:N-Acetylglucosaminyltransferases; C045073:Cre recombinase; D019426:Integrases