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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054716-03
Application #
6381356
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Linder, Barbara
Project Start
1999-09-01
Project End
2003-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
3
Fiscal Year
2001
Total Cost
$302,758
Indirect Cost
Name
Dartmouth College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
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

Showing the most recent 10 out of 17 publications