Human infertility and pregnancy loss represent major public health problems in women. Our long- range goal is to discover and understand the hormonal, cellular, and molecular mechanisms regulating uterine morphogenesis and function in order to provide fundamental information useful for prevention and clinical treatment of women's health problems. The success of developmental mechanisms regulating uterine morphogenesis dictates, in part, the embryotrophic potential and functional capacity of the adult uterus. In humans, uterine morphogenesis begins late in fetal life and is not completed until after birth, thereby precluding study of this critical process. Therefore, the proposed research will utilize mice as a model system to investigate genes governing uterine morphogenesis and function. The focus of this proposal is on Wnt7a, a gene that encodes a secreted protein that is expressed specifically in the epithelium of the developing and adult uterus. Genome- wide disruption of Wnt7a results in infertility due to uterine and oviductal malformations arising from developmental defects in Mullerian duct patterning and specification in the embryo. The central hypothesis is that Wnt7a is a critical regulator of postnatal endometrial gland morphogenesis and stromal growth and uterine receptivity to the embryo during pregnancy. In order to circumvent the developmental defects when Wnt7a is deleted in the embryo, we propose to conditionally ablate Wnt7a in the epithelium of the uterus after birth using the Cre/LoxP system and the innovative progesterone receptor-Cre knockin mouse model. The progesterone receptor is only expressed in the epithelium of the uterus after birth and is not expressed during Mullerian duct differentiation. The conditional mutant mice will be used to test our central hypothesis and understand the biological roles of Wnt7a in postnatal uterine morphogenesis, endometrial regeneration and adult uterine function. Accomplishment of these research goals is expected to significantly advance our understanding of the developmental aspects of uterine biology, determinants of adult uterine function, and provide a foundation for the design of clinical therapies to prevent, identify and treat human reproductive problems, such as infertility and pregnancy loss, due to uterine dysgenesis, dysplasia or dysfunction. This research will advance our understanding of the how the uterus develops. Abnormal development of the uterus can cause infertility and pregnancy loss in women. This research will help determine important genes for reproduction and help to design clinical therapies to prevent, identify and treat reproductive problems in women. ? ? ?
| Cooke, Paul S; Spencer, Thomas E; Bartol, Frank F et al. (2013) Uterine glands: development, function and experimental model systems. Mol Hum Reprod 19:547-58 |
| Spencer, Thomas E; Dunlap, Kathrin A; Filant, Justyna (2012) Comparative developmental biology of the uterus: insights into mechanisms and developmental disruption. Mol Cell Endocrinol 354:34-53 |
| Filant, Justyna; Zhou, Huaijun; Spencer, Thomas E (2012) Progesterone inhibits uterine gland development in the neonatal mouse uterus. Biol Reprod 86:146, 1-9 |
| Dunlap, Kathrin A; Filant, Justyna; Hayashi, Kanako et al. (2011) Postnatal deletion of Wnt7a inhibits uterine gland morphogenesis and compromises adult fertility in mice. Biol Reprod 85:386-96 |
| Hayashi, Kanako; Erikson, David W; Tilford, Sarah A et al. (2009) Wnt genes in the mouse uterus: potential regulation of implantation. Biol Reprod 80:989-1000 |
