Oocytes lacking O‐glycans alter follicle development and increase fertility by increasing follicle FSH sensitivity, decreasing apoptosis, and modifying GDF9:BMP15 expression

• Published in: The FASEB journal 2015-02, Vol.29 (2), p.525-539
• Main Authors: Grasa, Patricia, Ploutarchou, Panayiota, Williams, Suzannah A.
• Format: Article
• Language: English
• Subjects: Alleles; Animals; Apoptosis; bcl-2-Associated X Protein - metabolism; Bone Morphogenetic Protein 15 - metabolism; Clgalt1; endocrine profile; Estrous Cycle; Female; Fertility; Follicle Stimulating Hormone - metabolism; Gene Expression Regulation; Genotype; Growth Differentiation Factor 9 - metabolism; Mice; Mutation; Oocytes - cytology; Ovarian Follicle - metabolism; ovary; Ovary - metabolism; ovulation rate; Phenotype; Polysaccharides - chemistry; Proto-Oncogene Proteins c-bcl-2 - metabolism; T‐syn
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.14-253757

ABSTRACT The number of eggs ovulated varies within and between species and is influenced by many variables. However, the regulatory mechanisms remain poorly understood. We previously demonstrated a key role for the oocyte because mice generating oocytes deficient in core 1‐derived O‐glycans ovulate ~40‐50% more eggs than Controls. Here we analyze the basis of this phenotype using Mutant [core 1 β1, 3‐galactosyltransferase 1 (C1galt1)FF: zona pellucida glycoprotein 3 Cre (ZP3Cre)] and Control (C1galt1FF) female mice. In culture, Mutant follicles exhibited delayed antrum formation [indicative of follicle stimulant hormone (FSH) dependence] and increased sensitivity to FSH. Although the Mutant estrous cycle was extended, comprehensive endocrine changes were not observed; rather FSH, LH, inhibin B, and anti‐Mullerian hormone were temporally altered, revealing estrous cycle stage‐specific modifications to the hypothalamic‐pituitarygonadal axis. At proestrus, when FSH levels were decreased in Mutants, ovaries contained more, smaller, preantral follicles. Mutant follicles exhibited reduced levels of apoptosis, and both B‐cell lymphoma 2 (Bcl‐2) and BCL‐2‐associated X protein (Bax) were altered compared with Controls. Mutant ovaries also had an increase in the expression ratio of growth differentiation factor 9 (GDF9): bone morphogenetic protein 15 (BMP15) at diestrus. On the basis of these data, we propose that modified oocyte glycoproteins alter GDF9:BMP15 expression modifying follicle development resulting in the generation of more follicles. Thus, the oocyte is a key regulator of follicle development and has a crucial role in determining ovulation rate.—Grasa, P., Ploutarchou, P., Williams, S. A. Oocytes lacking O‐glycans alter follicle development and increase fertility by increasing follicle FSH sensitivity, decreasing apoptosis, and modifying GDF9:BMP15 expression. FASEB J. 29, 525‐539 (2015). www.fasebj.org