JoAnne S. Richards, Ph.D.
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