Functional Role of Wnt11 in Uterine Development and Adult Function

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DESCRIPTION (provided by applicant): 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 adult 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 Wnt11, a gene that encodes a secreted glycoprotein that is expressed specifically in the epithelium of the developing and adult uterus. Genome-wide disruption of Wnt11 results in perinatal lethality. The central hypothesis is that Wnt11 is a critical regulator of postnatal uterine development and adult uterine function. In order to circumvent the perinatal lethality of Wnt11-null mice, we will conditionally ablate Wnt11 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 M¿llerian duct differentiation. The conditional mutant mice will be used to test our central hypothesis and understand the biological roles of Wnt11 in postnatal uterine development 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.