Life without thyroid hormone receptors

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Cell and Molecular Biology

Sammanfattning: Thyroid hormone (TH) has many important functions during development and in the adult individual. It reaches its target cells via the blood system and binds its receptor (TR) located within the cell nucleus where the receptor regulates target genes. This hormone-mediated gene regulation is a finely tuned interplay of numerous parameters. These include i) usage of several isoforms of receptors (TRa1, TRb1, TRb2, TRb3) encoded for by two distinct genes, ii) receptor-mediated repression of target gene expression in the absence and activation in the presence of T3, and iii) enzymatic control of the relative concentrations of the active thyroid hormone (T3) versus prohormone (T4) through deiodinase activity. There are also target genes that respond in the opposite way to T3. This thesis describes mice that live without TRs. What have we learned from them? The mice show a milder phenotype than mice with a congenital incapacity of producing T3. In contrast to not having T3, being without TRs is less severe. This is due to the ability of TRs to act as potent transcription factors in the absence of hormone. The mice devoid of all known TRs were generated from mice lacking either the TRa or the TRb gene. Since deficiency for either single TR gene resulted in a much weaker phenotype as compared to fully TR deficient animals, our data indicate that the TR isoforms can substitute for each other in a variety of physiological and developmental functions. Despite the importance of T3, life is possible without TRs. However, the absence of TRs leads to an extreme dysregulation of T3 and retarded growth. T3 is important for skeletal development. It acts via growth hormone (GH) and insulin-like growth factor 1 (IGF-1). However, whether it has a direct effect on bone has been the subject of controversy. The mice lacking all TRs exhibit retarded bone development combined with low levels of GH and IGF-1. Supplementing the mice with GH normalises growth, suggesting that the retarded growth is caused by the low production of GH and IGF-1. However, the defective ossification in the epiphyses was not rescued by GH, which supports the hypothesis that T3 exhibits a direct effect on bone. Effects of T3 on brain development are known clinically from neurologic cretinism derived from low foetal T3 hormone levels and which leads to an almost vegetative life. The effects of T3 has been extensively studied particularly on cerebellar development. We therefore aimed to determine if T3 has any effect on the adult brain. Assaying solely for rapid responses in the cerebrum, we found almost 150 genes responding to T3, and notably, a third of these were also observed in mice having no TRs.

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