Genomic imprinting contributes to thyroid hormone metabolism in the mouse embryo.
Many genes subject to genomic imprinting function in a number of endocrine/paracrine pathways that are important for normal mammalian development. Here, we show that an endocrine/paracrine pathway involving thyroid hormone metabolism is also regulated by imprinting. Thyroid hormone action depends on thyroid hormone receptors and their predominant ligand, 3,5,3'-triiodothyronine (T3). In vivo, thyroid hormone levels are maintained within the physiological range through the interaction of three iodothyronine deiodinases, D1, D2, and D3. D3 inactivates thyroxine (T4) and T3 by 5-deiodination, and the gene for this enzyme, Dio3, lies in the imprinted domain on human chromosome 14q32/distal mouse chromosome 12. Here, we report the imprinting of Dio3, which is expressed preferentially from the paternal allele. No differentially methylated region was identified in the CpG-island promoter, which is completely unmethylated. Localization of transcripts suggests that Dio3 may be exerting its function in both endocrine and autocrine/paracrine manners. An assay was developed for T3, and we show that its levels in maternal and paternal uniparental disomy (UPD) 12 fetuses are reciprocally affected. These results demonstrate that disruption of the imprinting status of Dio3 results in abnormal thyroid hormone levels and may contribute to the phenotypic abnormalities in UPD12 mice and UPD14 humans.
Tsai
Chen En
CE
Department of Anatomy, University of Cambridge, Downing Street, United Kingdom.
Lin
Shau-Ping
SP
Ito
Mitsuteru
M
Takagi
Nobuo
N
Takada
Shuji
S
Ferguson-Smith
Anne C
AC
D000818:Animals; D004622:Embryo, Mammalian / Q000378:metabolism*; D018392:Genomic Imprinting; D017403:In Situ Hybridization; D051379:Mice; D013963:Thyroid Hormones / Q000378:metabolism*
D013963:Thyroid Hormones