Successful reproduction requires the cyclical growth differentiation, and death of cells in the ovary and uterus. These complex developmental processes are initiated by gonadotropic hormones from the pituitary and steroids from the ovary, but they are ultimately carried out by locally- produced growth factors. Many of the latter, including the fibroblast growth factors (FGFs), show distinct temporal and spatial patterns of expression in the ovary and uterus during the reproductive cycle or in response to hormonal stimulation. Physical and pharmacological ablation have defined many of the roles of the endocrine hormones in these processes, but those of the growth factors are less amenable to this approach: their roles can only be speculated at based on correlative expression studies. However, new transgenic techniques make it possible to precisely define the functions of FGFs during developmental processes. Studies in this laboratory show that cell-specific targeting of dominant- negative (dom-neg) FGF receptors (FGFRs) in reproductive tissues of transgenic mice is feasible. The goal of this study is to use dom-neg FGFRs, their expression targeted and controlled by cell-specific promoters, to inhibit the actions of FGFs at specific sites and times in the ovary and uterus. The study has four Specific Aims:
Aim 1 : To identify and localize FGFR subtypes in the mouse ovary and uterus.
Aim 2 :a) To produce mice that express dom-neg receptors for keratinocyte growth factor (KGF), an epithelial cell-specific FGF, and basic FGF (bFGF) in the epithelial cells of the endometrium using a 404 bp fragment of the uteroglobin promoter; and b) to evaluate uterine function in these mice.
Aim 3 :a) To produce mice that express dom-neg receptors for KGF and bFGF in the granulosa cells of the growing ovarian follicle using the -180 bp fragment of the Muellerian inhibiting substance promoter; and b) to evaluate ovarian function in these mice.
Aim 4 :a) To produce mice in which the expression of dom-neg FGFRs in the ovary and uterus can be temporarily controlled through tetracycline-responsive regulatory elements; and b) to evaluate the impact on fertility of switching on expression of dom-neg FGFRs in either the ovary or uterus at critical periods in the reproductive process (e.g., during follicular maturation or at the time of implantation). These studies will enhance our understanding of normal reproductive physiology as well as shed light on malfunctions in cell growth and differentiation in the ovary and uterus that lead to infertility, birth defects, and disease.
Showing the most recent 10 out of 41 publications
