Björn Vennström, professor emeritus
The research focuses on how thyroid hormone regulates developmental and metabolic processes. By using knock out mice deficient thyroid hormone receptor TRalpha1, TRbeta, or both TRs, we have identified the major roles for TRalpha-1 and TRbeta in different tissues.
The current projects aim to determine the mechanisms for how hypothyroidism causes its deleterious effects during fetal and postnatal development, and in the adult. For this, a mutation that decreases 10-fold the affinity of TRalpha1 for ligand was inserted into the corresponding mouse gene. These mice present several features characteristic of a receptor-mediated hypothyroidism: delayed postnatal development and ossification, hypermetabolism, and resistance to obesity. CNS dysfunctions include reduced cognition, locomotor perturbances, altered susceptibility to seizure inducing agents and a high anxiety. Many of the phenotypes mentioned above are caused by the mutant receptors ability to severely affect development of parvalbumin+ subclass of interneurons. Surprisingly, the thyroid-pituitary-hypothalamic axis shows only modest alterations. The project with the mutant TRalpha1 mice aimed to provide information allowing identification of patients harboring a similar mutation. Indeed, in 2012 the first four patients were identified by scientists in Great Britain and the Netherlands. The phenotypes of the patients mirror that found for the mutant mice, and treatment procedures used in our animal studies have been successfully adopted to the patient situations. Our current projects concern the effects of receptor mediated hypothyroidism on neuronal development, especially hypothalamic cells.
The thyroid hormone receptor alpha1 protein is expressed in embryonic postmitotic neurons and persists in most adult neurons.
Mol. Endocrinol. 2010 Oct;24(10):1904-16
Hypermetabolism in mice caused by the central action of an unliganded thyroid hormone receptor alpha1.
EMBO J. 2007 Oct;26(21):4535-45
Anxiety, memory impairment, and locomotor dysfunction caused by a mutant thyroid hormone receptor alpha1 can be ameliorated by T3 treatment.
Genes Dev. 2005 Sep;19(18):2152-63
Retardation of post-natal development caused by a negatively acting thyroid hormone receptor alpha1.
EMBO J. 2002 Oct;21(19):5079-87