Female Reproductive Tract

Wnt7a Is a Suppressor of Cell Death in the Female Reproductive Tract and Is Required for Postnatal and Estrogen-Mediated Growth

Abstract
The murine female reproductive tract is undifferentiated at birth and undergoes pronounced growth and cytodifferentiation during post-natal life. Post-natal reproductive tract development proceeds in the absence of high levels of circulating estrogens and is disrupted by precocious exposure to estrogens. The WNT gene family is critical in guiding the epithelial-mesenchymal interactions that direct postnatal uterine development. We had previously described a role for Wnt7a in controlling morphogenesis in the uterus. In addition to patterning defects, Wnt7a mutant uteri are atrophic in adults and do not show robust postnatal growth. We have examined immature female Wnt7a mutant and wildtype uteri to assess the cellular processes that underlie this failure in post-natal uterine growth. Levels of proliferation are higher in wildtype versus Wnt7a mutant uteri. Exposure to the potent estrogen agonist, diethylstilbestrol (DES), leads to an increase in cell proliferation in the uterus in wildtype as well as mutant uteri indicating that Wnt7a is not required in mediating cell proliferation. In contrast, we observe that Wnt7a mutant uteri display high levels of cell death in response to DES whereas wildtype uteri display almost no cell death revealing that Wnt7a plays a key role as a cell death suppressor. The expression pattern of other key regulatory genes that guide uterine development including the estrogen receptor (), Hox and other WNT genes reveals either an abnormal spatial distribution of transcripts or abnormal regulation in response to DES exposure. Taken together, this study demonstrates that Wnt7a coordinates a variety of cell and developmental pathways that guide post-natal uterine growth and hormonal responses and that disruption of these pathways leads to aberrant cell death.

Key words: Female Reproductive Tract • Apoptosis • Developmental biology • Estradiol • Mullerian ducts

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