Progesterone Receptor - a master regulator in the ovary and oviduct during the periovulatory period. (#133)
Ovulation requires sequential molecular events and structural remodelling for the successful release of a fertilisable oocyte. Critical to this process is progesterone receptor (PGR), a transcription factor highly yet transiently expressed in granulosa cells (GCs) of preovulatory follicles and abundant in the oviduct. PR-/- mice are anovulatory, despite normal growth/development of ovarian follicles and oocytes (1, 2). However, the mechanisms preventing follicle rupture and oocyte release are not understood. We identified PGR-regulated processes at multiple levels. In PR-/- and PR+/- ovaries 2h pre-ovulation, we found differential expression in genes involved in immune function using Low-Density Arrays, including down-regulation in PR-/- of vasoconstrictors (e.g. Edn1, 1.6-fold), cytokines (e.g. Il6, 4.5-fold), endothelial adhesion receptors (e.g. Sele, 2.4-fold) and Ptgs2 (3.5-fold). In GCs and cumulus-oocyte-complexes (COCs) isolated 8h post-hCG, microarray analysis identified 296 and 44 differentially expressed genes respectively. Gene ontology analysis revealed associations with cell adhesion, migration and invasion (e.g. Cxcr4, Zbtb16, Vcan, Actn4, Vcl, Amigo2, Epas1, Rasgrf2), processes found in periovulatory COCs (3). Mitochondrial membrane potential was altered in PR-/- oocytes compared to PR+/- (n=58-61 oocytes from 4 animals/genotype; P<0.0001), which is linked to compromised developmental competence (4). The importance of highly expressed PGR in the oviduct has previously been overlooked. We examined PR-/- and PR+/- periovulatory oviducts by microarray, identifying 1003 PGR-regulated genes, many associated with the functions of cell adhesion, migration, invasion; chemotaxis, muscle contraction and vasoconstriction. Several were validated as down-regulated in PR-/- oviducts by RT-PCR, including Adamts1 (3.7-fold), Itga8 (11.8-fold) and Edn3 (20.3-fold) and, in PR+/- oviducts, were induced by hCG/LH. Our identification of novel gene targets for PGR regulation in the ovary and oviduct exposes several new, down-stream influences of PGR on inflammation, the COC and oviductal function, highlighting the essential role of PGR as master regulator in the ovary and oviduct during the periovulatory period.
- Lydon et al, 1995, Genes Dev
- Robker et al, 2000, PNAS
- Akison et al, 2012, BOR
- Van Blerkom, 2011, Mitochondrion