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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG013784-08
Application #
6626438
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Bellino, Francis
Project Start
1995-09-01
Project End
2003-12-31
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
8
Fiscal Year
2003
Total Cost
$352,404
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Biology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Kurita, Takeshi; Mills, Alea A; Cunha, Gerald R (2004) Roles of p63 in the diethylstilbestrol-induced cervicovaginal adenosis. Development 131:1639-49
Carta, Luca; Sassoon, David (2004) Wnt7a is a suppressor of cell death in the female reproductive tract and is required for postnatal and estrogen-mediated growth. Biol Reprod 71:444-54
Mericskay, Mathias; Kitajewski, Jan; Sassoon, David (2004) Wnt5a is required for proper epithelial-mesenchymal interactions in the uterus. Development 131:2061-72
Kurita, T; Cooke, P S; Cunha, G R (2001) Epithelial-stromal tissue interaction in paramesonephric (Mullerian) epithelial differentiation. Dev Biol 240:194-211
Kurita, T; Lee, K; Saunders, P T et al. (2001) Regulation of progesterone receptors and decidualization in uterine stroma of the estrogen receptor-alpha knockout mouse. Biol Reprod 64:272-83
Kurita, T; Wang, Y Z; Donjacour, A A et al. (2001) Paracrine regulation of apoptosis by steroid hormones in the male and female reproductive system. Cell Death Differ 8:192-200
Kitajewski, J; Sassoon, D (2000) The emergence of molecular gynecology: homeobox and Wnt genes in the female reproductive tract. Bioessays 22:902-10
Kurita, T; Lee, K J; Cooke, P S et al. (2000) Paracrine regulation of epithelial progesterone receptor by estradiol in the mouse female reproductive tract. Biol Reprod 62:821-30
Kurita, T; Lee, K J; Cooke, P S et al. (2000) Paracrine regulation of epithelial progesterone receptor and lactoferrin by progesterone in the mouse uterus. Biol Reprod 62:831-8
Sassoon, D (1999) Wnt genes and endocrine disruption of the female reproductive tract: a genetic approach. Mol Cell Endocrinol 158:1-5

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