| Author: | Cai, Xiaojun |
| Title: | Characterization of ovarian functions in mouse models of granulosa cell-specific knockout of Abcc4 |
| Advisors: | Ruan, Y. C. Sharon (BME) |
| Degree: | M.Sc. |
| Year: | 2024 |
| Subject: | Ovaries -- Diseases -- Animal models Ovaries -- Diseases -- Treatment Hong Kong Polytechnic University -- Dissertations |
| Department: | Department of Biomedical Engineering |
| Pages: | iv, 46 pages : color illustrations |
| Language: | English |
| Abstract: | For recent decades, infertility has become a global health issue, affecting one in six people worldwide. Ovarian dysfunction, such as in polycystic ovary syndrome and primary ovarian insufficiency, is a leading cause for female infertility. The ovary is the key component of the female reproduction system indispensable for the growth and maturation of the oocyte in an anatomic structure called follicle, so-called folliculogenesis, as well as the production of ovarian steroids (e.g., estrogen, progesterone), the so-called steroidogenesis. Granulosa cells, the epithelial-like ovarian somatic cells surrounding the oocyte in developing follicles, play crucial roles in both folliculogenesis and steroidogenesis. Multi-drug resistance protein 4 (MRP4), also known as ATP-binding cassette (ABC) transporter superfamily member 4, encoded by the human gene ABCC4, is best known for its function in excluding cytotoxic drugs/small molecules, and therefore proposed as a target in improving chemotherapy treatments. However, though its role in transporting endogenous molecules such as cAMP and prostaglandins is noted, the physiological roles of MRP4 remain largely unexplored. Given that prostaglandins play essential roles in ovarian functions, we hypothesized that MRP4 might be expressed in ovarian granulosa cells to play a role in ovarian functions in folliculogenesis and steroidogenesis. In the present study, we utilized two granulosa cell-specific Cre models, Cyp19a1cre and AMHcre, to cross with a transgenic mouse line with Abcc4 exon flanked by LoxP sites (Abcc4fl/fl), and successfully created two mouse models of granulosa cell-specific knockout of MRP4 (Abcc4fl/flCyp19a1cre and Abcc4fl/flAMHcre). Folliculogenesis and steroidogenesis functions were examined in the two models and compared with the Cre-negative control (Abcc4fl/fl) mice. Follicles at different developmental stages, namely, primary, secondary, preantral, early antral and late antral follicles were identified through morphological assessment of ovarian sections from the models. As compared to the control, both Abcc4fl/flCyp19a1cre and Abcc4fl/flAMHcre mice showed a decreased number of late antral follicles, suggesting a role of MRP4 in late folliculogenesis. Daily vaginal spear and cytology were performed in the mice to identify stages of estrus cycle, namely, proestrus, estrus, metestrus and diestrus, to evaluate steroid homeostasis in the mice. Results showed that, as compared to the control group (Abcc4fl/fl), the estrous cycles of Abcc4fl/flCyp19a1cre and Abcc4fl/flAMHcre mice were disrupted with significantly shortened estrus phase. In addition, the blood level of estradiol at the estrus and diestrus stages was measured in mice of different genotypes. Results showed that both Abcc4fl/flCyp19a1cre and Abcc4fl/flAMHcre mice had higher blood levels of estradiol, as compared with the control mice (Abcc4fl/fl). Taken together, these results have suggested that MRP4 in granulosa cells may play a critical role in both folliculogenesis and steroidogenesis functions of the ovary, which may provide new insights into the understanding of granulosa cells in ovarian physiology and possibly ovarian disorders. |
| Rights: | All rights reserved |
| Access: | restricted access |
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| File | Description | Size | Format | |
|---|---|---|---|---|
| 7410.pdf | For All Users (off-campus access for PolyU Staff & Students only) | 1.45 MB | Adobe PDF | View/Open |
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