Abstract
The Dio3 gene, which encodes for the type 3 deiodinase (D3), controls thyroid hormone (TH) availability. The lack of D3 in mice results in tissue overexposure to TH and a broad neuroendocrine phenotype. Dio3 is an imprinted gene, preferentially expressed from the paternally inherited allele in the mouse fetus. However, heterozygous mice with paternal inheritance of the inactivating Dio3 mutation exhibit an attenuated phenotype when compared with that of Dio3 null mice. To investigate this milder phenotype, the allelic expression of Dio3 was evaluated in different mouse tissues. Preferential allelic expression of Dio3 from the paternal allele was observed in fetal tissues and neonatal brain regions, whereas the biallelic Dio3 expression occurred in the developing eye, testes, and cerebellum and in the postnatal brain neocortex, which expresses a larger Dio3 mRNA transcript. The newborn hypothalamus manifests the highest degree of Dio3 expression from the paternal allele, compared with other brain regions, and preferential allelic expression of Dio3 in the brain relaxed in late neonatal life. A methylation analysis of two regulatory regions of the Dio3 imprinted domain revealed modest but significant differences between tissues, but these did not consistently correlate with the observed patterns of Dio3 allelic expression. Deletion of the Dio3 gene and promoter did not result in significant changes in the tissue-specific patterns of Dio3 allelic expression. These results suggest the existence of unidentified epigenetic determinants of tissue-specific Dio3 imprinting. The resulting variation in the Dio3 allelic expression between tissues likely explains the phenotypic variation that results from paternal Dio3 haploinsufficiency.
Highlights
The Dio3 gene, which encodes for the type 3 deiodinase (D3), controls thyroid hormone (TH) availability
We have shown that mice lacking D3 (D3KO or Dio3Ϫ/Ϫ mice) are overexposed to T3 during development and subsequently manifest marked deficits in the maturation and function of the thyroid axis, severe growth retardation, and impaired viability and fertility [8, 9]
In the context of the milder gross phenotype that we observe in heterozygous mice with a mutated paternal Dio3 allele when compared with that of null Dio3 mice, we use our previously described D3KO mouse and a second novel model of targeted Dio3 disruption to analyze Dio3 allelic expression in various tissues and in regions of the central nervous system (CNS)
Summary
First Published Online September 18, 2014 for the maintenance of appropriate levels of TH in the fetus and the adult In this regard, we have shown that mice lacking D3 (D3KO or Dio3Ϫ/Ϫ mice) are overexposed to T3 during development and subsequently manifest marked deficits in the maturation and function of the thyroid axis, severe growth retardation, and impaired viability and fertility [8, 9]. We have reported a lesser degree of genomic imprinting in the heads of fetal mice [17] Taken together, these observations suggest that allelic contributions to Dio expression vary in a tissue-specific pattern, with resultant functional and phenotypic implications. This suggests that epigenetic information regulates Dio expression in a tissue- and/or cell-specific manner and that the resultant alterations in the imprinting pattern of Dio effect developmental outcomes
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