Hypothyroidism Caused by a Mutant Thyroid Hormone Receptor α1

Lack of sufficient thyroid hormone during pregnancy and early postnatal development results in profound mental retardation and motor deficits whereas altered thyroid status in the adult is associated with disturbed metabolic homeostasis and impaired cardiac function. Thyroid hormone mediates its effects through the distinct thyroid hormone receptors (TR) TR 1 and TR 1-2, which are ligand-modulated transcription factors that regulate gene expression both in the presence and absence of hormone. Mutations in the TR gene that decrease affinity to ligand are associated with the well known syndrome Resistance to thyroid hormone (RTH), which is characterized by elevated circulating levels of thyroid hormone and a mixed hyperand hypothyroid phenotype. However, no patient with a corresponding mutation in the TR gene has been found. In this thesis, I describe the developmental and physiological consequences of a point mutation introduced into the mouse TR 1 gene. The mutation, originally identified in TR (R438C) of RTH patients, reduces affinity for T3 10-fold, and causes the receptor to act as an aporeceptor unless challenged with high levels of thyroid hormone. We report that mice heterozygous for this mutation (TR 1+m mice) exhibit locomotor dysfunctions caused by insufficient supply of thyroid hormone during fetal/postnatal development. Furthermore, treatment with thyroid hormone during specific stages of development ameliorated these deficiencies. The locomotor dysfunctions correlated with delayed or perturbed development of several brain regions. Notably, we report that specific GABAergic cells in the neocortex were affected: the appearance of parvalbumin-immunoreactive GABAergic interneurons was severely delayed whereas the numbers of calretinin-immunoreactive cells were increased. The TR 1+m mice also exhibited increased metabolic rate, hyperphagia and resistance to obesity despite their reduced body temperature. This is likely due to increased hypothalamic output to brown adipose tissue: adaptation to thermoneutrality normalized most metabolic parameters. Further analysis of hypothalamic function in the TR 1+m mice supports this view. Finally, we demonstrate that the mutant TR 1 severely affects calcium handling in mouse cardiomyocytes, which in larger organisms may result in heart disease. In conclusion, we have identified novel and important properties of the TR 1 aporeceptor in neuronal development as well as in physiological processes such as thermogenesis and cardiac function. That the mutant mice have normal serum levels of thyroid hormone offers an explanation for why corresponding patients have not been found. However, our data provide information potentially critical for identification of patients and for their treatment. LIST OF PUBLICATIONS This thesis is based on the following papers, which will be referred to in the text by their Roman numerals: I. Karin Wallis*, Maria Sjogren*, Max van Hogerlinden, Gilad Silberberg, Andre Fisahn, Kristina Nordstrom, Lars Larsson, Hakan Westerblad, Gabriela Morreale de Escobar, Oleg Shupliakov and Bjorn Vennstrom. Locomotor deficiencies and aberrant development of subtype-specific GABAergic interneurons caused by an unliganded thyroid hormone receptor 1. Accepted for publication in The Journal of Neuroscience 2008. II. Maria Sjogren*, Anneke Alkemade*, Jens Mittag, Kristina Nordstrom, Abram Katz, Bjorn Rozell, Hakan Westerblad, Anders Arner and Bjorn Vennstrom. Hypermetabolism in mice caused by the central action of an unliganded thyroid hormone receptor 1. The EMBO Journal (2007) 26, 4535-45. III. Anneke Alkemade, Maria Sjogren, Kristina Nordstrom and Bjorn Vennstrom. Unliganded thyroid hormone receptor 1 disrupts the neuroendocrine response to fasting. Manuscript 2007. IV. Pasi Tavi, Maria Sjogren, Per Kristian Lunde, Shi-Jin Zhang, Fabio Abbate, Bjorn Vennstrom and Hakan Westerblad. Impaired Ca2+ handling and contraction in cardiomyocytes from mice with a dominant negative thyroid hormone receptor 1. Journal of Molecular and Cellular Cardiology (2005) 38, 655-63. * Equal contribution