Thyroid hormones (TH) play an important role in development in humans and other vertebrate species by influencing growth and differentiation of a number of tissues including the brain. The type 3 deiodinase (D3) is a selenoenzyme that inactivates TH and is highly expressed in the pregnant uterus, placenta and in fetal and neonatal tissues. The Dio3 gene, which encodes this enzyme, is imprinted in the mouse fetus, as are select other genes important in growth and development. We hypothesize that the expression and regulation of D3 in the utero/placental/fetal unit is critically important for maintaining the required levels of TH during development, and that this enzyme prevents the premature exposure of fetal and neonatal tissues to the differentiating effects of TH. In this proposal we plan to take advantage of the genetic mouse models of D3 deficiency which we have recently developed using homologous recombination techniques to address the following specific aims: (1) to determine the functional significance of D3 expression during development; (2) to define the mechanisms and etiology of alterations in the serum TH levels observed in the D3-deficient mouse model; and (3) to determine the functional significance of inducing D3 deficiency at different stages of development and during adulthood. These aims will be addressed by characterizing in detail the phenotypes of our model systems using functional assays that test neurological, metabolic, and reproductive functions; anatomical methods that will allow us to identify structural abnormalities at the gross and microscopic levels, and molecular techniques that will provide mechanistic information regarding the role of the D3 during development. Preliminary studies on D3-deficient mice have already identified several phenotypic abnormalities including hypothyroidism that appears to be central in origin, growth retardation, impaired fertility, and increased perinatal mortality. The additional studies outlined in this proposal to further characterization these and other phenotypic abnormalities will likely provide important new insights into growth, development and reproductive and thyroid function in humans.