This proposal extends our ongoing investigation into the molecular basis of cellular interactions that guide the proper development and adult function of the female reproductive tract. We have demonstrated that Wnt genes direct the proper cytodifferentiation and overall development of the female reproductive tract. Analyses of two WNT mouse mutants (Wnt7a and Wnt5a) has confirmed that Wnt gene activity is not only crucial for proper development but also participates in regulating adult function including changes that occur during estrous in the uterus, cervix and vagina. The fact that circulating steroid hormones regulate Wnt gene expression led us to investigate how exogenous estrogenic compounds may adversely affect reproductive tract development. Diethylstilbestrol (DES) is a synthetic estrogen agonist, which was administered to pregnant women between 1940-1976. Daughters born to mothers who took DES experienced a high rate of reproductive tract malformations and a higher incidence of reproductive tract precancerous and cancer pathologies. We have demonstrated that Wnt7a is down-regulated by DES exposure during a critical perinatal period of perinatal development. Furthermore, since the transient down-regulation of Wnt7a recapitulates the effects of a complete loss-of-function of Wnt7a in the female reproductive tract, we conclude that the key molecular and cellular responses to Wnt genes occur at birth. This proposal will focus upon determining the signaling pathway(s) through which these crucial Wnt signals are transduced. We will also examine the role of Msx1, which is expressed in the reproductive tract and is a strong candidate for mediating specific aspects of Wnt signaling. Lastly, we plan to identify 'early' Wnt gene targets in the female reproductive tract that are regulated in response to these signaling events. It is anticipated that changes in gene expression will be both direct and indirect. In women, the pathological effects of fetal DES exposure were recognized several decades later in adult life. In mice, both the DES-exposed wildtype and Wnt7a mutant mouse show aberrant morphology by 1-2 months after birth and precancerous and bona fide tumors by 9-18 months after birth. Thus, the characterization of the genes whose expression is altered at birth as a function of loss of Wnt7a promises to lead to potential early diagnostic markers of cancer and help elucidate early steps in teratogenic and tumorogenic processes in the female reproductive tract. To this end, we will test the function of candidate Wnt7a target genes by direct gene transfer in vivo or use of available mouse mutants. It is anticipated that results from these studies will have a high impact upon our understanding of mechanisms underlying how complex intact tissues in vivo respond to normal hormonal signaling and that this mechanistic understanding will bear upon our understanding of clinical applications of hormone replacement therapies and endocrine disruption. ? ? ?
| Vandenberg, Alysia L; Sassoon, David A (2009) Non-canonical Wnt signaling regulates cell polarity in female reproductive tract development via van gogh-like 2. Development 136:1559-70 |
| Ma, Risheng; Sassoon, David A (2006) PCBs exert an estrogenic effect through repression of the Wnt7a signaling pathway in the female reproductive tract. Environ Health Perspect 114:898-904 |
