Embryonic development in mammals takes place within a maternal body cavity where various hormones and substances from the mother have the potential to impact on fetal growth and maturation. Such exposure to maternal compounds can have either beneficial or detrimental effects. Thus, the function of the uterus and placenta in regulating the flow of substances between the mother and fetus is crucial for fetal development. This appears to be of particular importance regarding thyroid hormones (TH), which exert profound effects on multiple tissues of the developing organism, including the brain. Thus, regulation of fetal thyroid hormone levels is of utmost importance to the orderly progression of developmental processes. The type 3 iodothyronine deiodinase (D3) catalyzes the conversion of thyroxine (T4) and 3,5,3'-triiodothyronine (T3) to inactive metabolites, and is highly expressed in the placenta. In addition, we have recently demonstrated that this enzyme is also present in the fetus at very early stages of development, and in the rodent uterus where its expression in decidual tissue appears to be markedly induced early in pregnancy. Later in gestation, D3 expression appears to shift to the epithelial cells lining the recanalized uterine lumen that surrounds the fetal membranes. We thus hypothesize that during embryogenesis, D3 expression in the uterus, placenta and fetus prevents the premature exposure of fetal tissues to the differentiating effects of TH. We further hypothesize, based on preliminary data, that growth factors and/or cytokines are important regulators of D3 expression during development. To test these hypotheses, we will: (1) delineate the expression patterns and regulation of D3 mRNA and activity in the rodent uterus; (2) define the cellular and temporal patterns of expression of the D3 in the uterus, placenta, fetus, and neonate during development using in situ hybridization, immunocytochemical methods, and a mouse model expressing a D3/LacZ fusion reporter gene; (3) determine the functional significance of D3 expression during development by creating and characterizing a D3 deficient mouse model, and (4) characterize a unique 3.2 kb D3-related transcript found in the human uterus. The results of these studies will provide important new insights, not only into the physiological role of the D3, but also into the importance and regulation of TH as an effector of critical developmental processes. Such insights into the basic processes controlling cellular proliferation and differentiation may have other important ramifications, given current interest in hormones as potential modifiers of neoplastic processes.
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