129. OVARIAN PHENOTYPE OF THE IKK CONDITIONAL KNOCKOUT MOUSE

Abstract

Nuclear factor-κB (NFκB) designates a family of transcription factors that has been shown to modulate antiviral, inflammatory and immune responses and promote tumorigenesis. Activation of NFκB is dependent on IKKβ, a component of the IκB kinase (IKK) complex which promotes degradation of IκB inhibitory proteins and allows nuclear translocation of NFκB. Little is known about the role of NFκB signalling in the ovary. We created a gonadal specific IKKβ conditional knockout mouse to explore NFκB action in the ovary. A transgenic mouse line containing floxed IKKβ alleles (M Karin, UCSD) was crossed with a transgenic mouse line expressing cre-recombinase under the control of the anti-Müllerian hormone receptor (AMHR) promoter (M Matzuk, BCM). Female mice arising from this breeding regime will not express IKKβ in granulosa cells and cannot activate NFκB signalling. Ovaries and serum were collected from mice at 7 and 15 weeks of age. Histological analyses were undertaken and the gonadotrophic hormones, follicle stimulating hormone (FSH) and luteinising hormone (LH) were measured. The ovaries of 7 week old IKKβ null mice contained follicles of all developmental stages although corpora lutea were absent indicating that these mice were infertile. Some follicle subtypes may be under-represented and apoptosis may be enhanced; these studies are ongoing. Serum FSH and LH levels were elevated compared to littermate controls. By 15 weeks of age corpora lutea were present. The fertility of the IKKβ conditional knockout is currently being assessed. In summary, IKKβ conditional knockout mice exhibit a reproductive phenotype which includes delayed ovulation. These results validate the hypothesis that ovulation is an inflammatory-like response. This model will be a valuable tool for reproductive research; the subtlety of the phenotype allowing us to tease out the underlying mechanisms and role of NFκB signalling in ovarian function.