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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Endocrinology Study Section (END)
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Sato, Sheryl M
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Dartmouth College
Internal Medicine/Medicine
Schools of Medicine
United States
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Wu, Zhaofei; Martinez, M Elena; St Germain, Donald L et al. (2017) Type 3 Deiodinase Role on Central Thyroid Hormone Action Affects the Leptin-Melanocortin System and Circadian Activity. Endocrinology 158:419-430
Martinez, M Elena; Karaczyn, Aldona; Stohn, J Patrizia et al. (2016) The Type 3 Deiodinase Is a Critical Determinant of Appropriate Thyroid Hormone Action in the Developing Testis. Endocrinology 157:1276-88
Martinez, M Elena; Charalambous, Marika; Saferali, Aabida et al. (2014) Genomic imprinting variations in the mouse type 3 deiodinase gene between tissues and brain regions. Mol Endocrinol 28:1875-86
Hernandez, Arturo; Quignodon, Laure; Martinez, M Elena et al. (2010) Type 3 deiodinase deficiency causes spatial and temporal alterations in brain T3 signaling that are dissociated from serum thyroid hormone levels. Endocrinology 151:5550-8
Boelen, Anita; Kwakkel, Joan; Wieland, Catharina W et al. (2009) Impaired bacterial clearance in type 3 deiodinase-deficient mice infected with Streptococcus pneumoniae. Endocrinology 150:1984-90
Lu, Ailing; Ng, Lily; Ma, Michelle et al. (2009) Retarded developmental expression and patterning of retinal cone opsins in hypothyroid mice. Endocrinology 150:1536-44
Galton, Valerie Anne; Schneider, Mark J; Clark, Ann S et al. (2009) Life without thyroxine to 3,5,3'-triiodothyronine conversion: studies in mice devoid of the 5'-deiodinases. Endocrinology 150:2957-63
St Germain, Donald L; Galton, Valerie Anne; Hernandez, Arturo (2009) Minireview: Defining the roles of the iodothyronine deiodinases: current concepts and challenges. Endocrinology 150:1097-107
Labialle, Stephane; Yang, Lanjian; Ruan, Xuan et al. (2008) Coordinated diurnal regulation of genes from the Dlk1-Dio3 imprinted domain: implications for regulation of clusters of non-paralogous genes. Hum Mol Genet 17:15-26
Hernandez, Arturo; Martinez, M Elena; Liao, Xiao-Hui et al. (2007) Type 3 deiodinase deficiency results in functional abnormalities at multiple levels of the thyroid axis. Endocrinology 148:5680-7

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