Department of Molecular & Cellular Biology
Dr. Richards's work focuses on molecular mechanisms by which pituitary gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH) regulate ovarian development, ovulation and luteinization. Her recent findings have opened new molecular frontiers for understanding ovulation and luteinization as well as ovarian cancer.
Dr. Richards and her colleagues recently described the roles of specific signaling molecules, the EGF-like factors, which are induced by the LH surge in preovulatory follicles. These factors activate a signaling cascade that serves as the major switch controlling the global, genetic reprogramming of cells in these follicles. Specifically, the signaling switch is essential for controlling the resumption of meiosis in oocytes, cumulus cell-oocyte complex expansion, ovulation and luteinization.
Two kinases (MAPK) and MAPK3/1 (also known as ERK1/2) were previously known to act as the critical control switches for meiosis resumption. The rationale for disrupting these two kinases was based on results from Dr. Richards's laboratory and that of others. However, the physiological functions of the EGF-like factors and their downstream targets, RAS and ERK1/2, during follicular development in vivo were unknown.
To address this question, Dr. Richards's lab generated a mutant mouse model in which both Erk1 and Erk2 were disrupted selectively in the preovulatory follicules. The Erk1/2 mutant mice were completely infertile. Resumption of meiosis in oocytes failed to occur and expansion of the cumulus cell-oocyte complex was blocked. Ovulation was completely impaired and luteinization (the transition of proliferating, estradiol producing granulosa cells to terminally differentiated, non-dividing luteal cell) was not initiated.
As a consequence, the ovaries of the Erk1/2 null mice contained normal growing and preovulatory follicles but no corpora lutea (a temporary endocrine structure essential for establishing and maintaining pregnancy). Gene profiling experiments documented further that the expression of many genes was disrupted in granulosa cells of the Erk1/2 mutant mice. Dr. Richards and her colleagues also documented that the transcription factor C/EBPβ, which mediates some of the effects of these kinases at the molecular level, regulates genes controlling ovulation and luteinziation.
These experiments provided novel data and a wealth of information on the critical importance of ERK1/2 for regulated gene expression at this unique stage of granulosa cell differentiation. The distinct effects of RAS and ERK1/2 in ovarian mesenchymal (granulosa) compared to epithelial cells are likely to have parallels and far-reaching consequences in other tissues.
Collectively, these studies provide ground-breaking information on events that control ovulation and luteinization that should help unravel the molecular basis causing infertility in many women. They also provide novel information that may lead to the design of new contraceptive approaches of for improving in vitro maturation of oocytes for IVF procedures.
Dr. Richards's nomination was based on the following publications:
Fan HY, Shimada M, Liu Z, Cahill N, Noma N, Wu Y, Gossen J, and Richards JS. Selective expression of KrasG12D in granulosa cells of the mouse ovary causes defects in follicle development and ovulation. Development 2008 135(12): 2127-2137.
Fan HY, Liu Z, Shimada M, Sterneck E, Johnson PF, Hedrick SM, and Richards JS. MAPK3/1 (ERK1/2) in ovarian granulosa cells are essential for female fertility. Science 2009 324:938-941.
Fan HY, Liu Z, Paquet M, Wang J, Lydon JP, DeMayo FJ, and Richard JS. Cell type-specific targeted mutations of Kras and Pten document proliferation arrest in granulosa cells versus oncogenic insult to ovarian surface epithelial cells. Cancer Res 2009 69(16): 6463-6472.