title: 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 postnatal life. Postnatal 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 have 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. In the present study, we examine immature female Wnt7a mutant and wild-type uteri to assess the cellular processes that underlie this failure in postnatal uterine growth. Levels of proliferation are higher in wild-type versus Wnt7a mutant uteri. Exposure to the potent estrogen-agonist diethylstilbestrol (DES) leads to an increase in cell proliferation in the uterus in wild-type as well as in 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 wild-type 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 estrogen receptor (alpha), Hox, and other WNT genes, reveals either abnormal spatial distribution of transcripts or abnormal regulation in response to DES exposure. Taken together, the results of the present study demonstrate that Wnt7a coordinates a variety of cell and developmental pathways that guide postnatal uterine growth and hormonal responses and that disruption of these pathways leads to aberrant cell death.
authors.affiliation: Brookdale Department of Developmental, Cellular and Molecular Biology, Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, NY 10029, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Carta
authors.forename: David
authors.initials: D
authors.lastname: Sassoon
mesh_terms: D000818:Animals; D016923:Cell Death / Q000502:physiology*; D002455:Cell Division; D004054:Diethylstilbestrol / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism*; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009095:Mullerian Ducts / Q000254:growth & development / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D014599:Uterus / Q000254:growth & development* / Q000473:pathology / Q000502:physiology*; D051153:Wnt Proteins
chemical_list: D004967:Estrogens; D004968:Estrogens, Non-Steroidal; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; C490508:Wnt7a protein, mouse; D004054:Diethylstilbestrol