The molecular basis of cellular interactions guiding the proper development and adult function of the female reproductive tract are not well understood. Until recently, the nature of the signals that guide the epithelial-mesenchymal interactions required for differentiation and reproduction has not been identified. This project stems from observations made by the applicant implicating the Wnt gene family which encodes essential signaling proteins that underlie the proper patterning of the uterus, cervix and vagina. The regulation of this genes is shared by developmental controls and by circulating steroid hormones. As such, the female reproductive tract is particularly vulnerable to perturbations caused by exogenous compounds with steroidogenic activity. These compounds, referred to as 'endocrine disrupters' are present either as environmental toxins or as pharmaceutical treatments. A formal link between in utero exposure to one such compound, DES, and malformations and cancers of the female reproductive tract has been well established although the molecular basis of these perturbations is poorly understood. At least 1 million women were exposed to DES in the USA alone. Disruption of nt7a, one member of the Wnt gene family expressed in the reproductive tract, results in a phenotype of the reproductive tract which is very similar to that found in DES exposed mice and humans. Furthermore, DES exposures leads to a down-regulation of Wnt7a in the female reproductive tract during a critical period of morphogenesis. This represents the first molecular 'target' identified to date in the DES syndrome. We have obtained mice carrying deletions for each of the three Wnt genes expressed in the murine female reproductive tract. The experiments proposed in this application will greatly extend these observations and will capitalize on several genetic models already generated by the applicant which reveal that de-regulation of multiple Wnt gene family members may account for numerous human pathologies of the female reproductive tract. In particular, mice carrying heterozygous deletions for Wnt7a and Wnt5a show overt histological signs of cystic glandular hyperplasia which affects a significant proportion of post- menopausal women. We will use genetic models and gene transfer methodologies to assess the role of each Wnt gene in the female reproductive tract, and further investigate how Wnt7a functions as a tumor suppressor. We will employ the p53 (tumor suppressor) mutant mouse to address the genetic pathway that connects endocrine disruption and deregulation of Wnt gene expression to the express of tumorigenesis which is observed in our model systems.
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