Priority Programme: THYROID TRANS ACT
Translation of Thyroid Hormone Actions beyond Classical Concepts

Dr. Eva K. Wirth, Prof. Dr. Ulrich Schweizer

Cell type-specific inactivation of Mct8 in brain cells: Gene expression, metabolism, morphology

Thyroid hormone (TH) transporters and among them monocarboxylate transporter 8 (MCT8) are necessary for proper brain development. Mutations in MCT8 lead to a severe form of psychomotor retardation in humans, the Allan-Herndon-Dudley syndrome (AHDS). Patients present with X-linked mental retardation, muscular hypotonia, and disturbed plasma TH levels (high T3, low T4). Mouse models for global Mct8-deficiency have been generated and yielded surprising data. Tissue responses to circulating TH levels depend on transporter expression leading to hepatic TH excess and concomitant pituitary insensitivity to TH. Similarly, biochemical and behavioural data suggest the coexistence of hyper- and hypothyroid regions in the brain. Thus, evidence is accumulating that the neurological deficits in AHDS patients are not simply caused by defective TH uptake into neurons. In order to better understand the neurological and neurobiochemical phenotypes, we want to take into account the complexity of the brain as an organ composed of neurons, astrocytes, oligodendrocytes, and endothelial cells.

We will therefore create astrocyte- and neuron-specific Mct8 knockout mice and re-investigate gene expression, energy metabolism, TH metabolism, and dendritic morphology in their brains. We will thus be able to distinguish metabolic impairments caused by astrocytic or neuronal TH insensitivity from a defective blood-brain-barrier in Mct8-deficient mice. Moreover, we will gain new insight into the compartmentalization of cerebral TH metabolism.

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Project Coordinator(s):

Dr. Eva K. Wirth
Charité - Universitätsmedizin Berlin
Institut für Experimentelle Endokrinologie
Augustenburger Platz 1
13353 Berlin
Phone: +49 30 450 524 105
Fax: +49 30 450 524 922
eva.wirth@charite.de

Prof. Dr. Ulrich Schweizer
Rheinische Friedrich-Wilhelms-Universität Bonn
Institut für Biochemie und Molekularbiologie
Nussallee 11
53115 Bonn
Phone: +49 228 73 4444
Fax: +49 228 73 4558
uschweiz@uni-bonn.de