Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Inactivation of the mgat1 gene in oocytes impairs oogenesis, but embryos lacking complex and hybrid N-glycans develop and implant Shi S, et al . Complex and hybrid N-glycans contain sugar residues that have been implicated in fertilization, compaction of the embryo, and implantation. Inactivation of the Mgat1 gene responsible for their synthesis is embryonic lethal, but homozygous mutant blastocysts are phenotypically normal due to the presence of maternal Mgat1 gene transcripts. To identify roles for complex and hybrid N-glycans in oogenesis and preimplantation development, the Mgat1 gene in oocytes was deleted by using a ZP3Cre recombinase transgene. All mutant oocytes had an altered zona pellucida (ZP) that was thinner than the control ZP, and they did not possess complex N-glycans but contained ZP1, ZP2, and ZP3 glycoproteins. Mutant eggs were fertilized, all embryos implanted, and heterozygotes developed to birth. However, mutant females had decreased fertility, yielded fewer eggs after stimulation with gonadotropins, and produced a reduced number of preimplantation embryos and less progeny than controls. About 25% of embryonic day 3.5 (E3.5) embryos derived from mutant eggs were severely retarded in development, even when they were heterozygous and expressed complex N-glycans. Thus, a proportion of Mgat1(-)(/)(-) oocytes were developmentally compromised. Surprisingly, mutant eggs also gave rise to Mgat1(-)(/)(-) embryos that developed normally, implanted, and progressed to E9.5. Therefore, complex or hybrid N-glycans are required at some stage of oogenesis for the generation of a developmentally competent oocyte, but fertilization, blastogenesis, and implantation may proceed in their absence.

Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: Oocyte-specific deletion of complex and hybrid N-glycans leads to defects in preovulatory follicle and cumulus mass development. Williams SA et al. Complex and hybrid N-glycans generated by N-acetylglucosaminyltransferase I (GlcNAcT-I), encoded by Mgat1, affect the functions of glycoproteins. We have previously shown that females with oocyte-specific deletion of a floxed Mgat1 gene using a ZP3Cre transgene produce fewer pups due primarily to a reduction in ovulation rate. Here we show that the ovulation rate of mutant females is decreased due to aberrant development of preovulatory follicles. After a superovulatory regime of 48 h pregnant mare's serum (PMSG) and 9 h human chorionic gonadotropin (hCG), mutant ovaries weighed less and contained ~60% fewer preovulatory follicles and more atretic and abnormal follicles than controls. Unlike controls, a proportion of mutant follicles underwent premature luteinization. In addition, mutant preovulatory oocytes exhibited gross abnormalities with ~36% being blebbed or zona-free. While 97% of wild type oocytes had a perivitelline space at the preovulatory stage, ~54% of mutant oocytes did not. The cumulus mass surrounding mutant oocytes was also smaller with a decreased number of proliferating cells compared to controls, although hyaluronan around mutant oocytes was similar to controls. In addition, cumulus cells surrounding mutant eggs were resistant to removal by either hyaluronidase or incubation with capacitated sperm. Therefore, the absence of complex and hybrid N-glycans on oocyte glycoproteins leads to abnormal folliculogenesis resulting in a decreased ovulation rate.

Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Premature Ovarian Failure in Mice with Oocytes Lacking Core 1-Derived O-Glycans and Complex N-Glycans. Williams SA et al. 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.

Species: mouse
Mutation name:
type: null mutation
fertility: subfertile
Comment: Dysregulation of follicle development in a mouse model of premature ovarian insufficiency. Grasa P et al. (2016) Premature ovarian insufficiency (POI) occurs in 1% of women of reproductive age. 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 sub-fertile 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 3B-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 to 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 etiology of a model of POI and highlight targets to investigate with the hope of developing new fertility treatments.//////////////////