Former research group (until 2017): environmentally-induced endocrine disruption

Head of research group:
Dr. rer. nat. Heike Heuer

Research profile

A main interest of our group is to define the role of thyroid hormones (TH) in brain development and to identify chemicals that compromise proper TH signaling in the CNS.  We are particularly interested in studying TH transporters that are mandatory for intracellular TH action and can therefore be considered as putative targets of endocrine disruptors.

In humans, inactivation of the TH transporter MCT8 leads to a severe form of psychomotor retardation (Allan-Herndon-Dudley syndrome (AHDS)). By studying mouse mutants that lack MCT8 in specific cell types and tissues we want to dissect the exact pathogenic mechanisms underlying this syndrome. Moreover, by taking advantage of our recently generated AHDS mouse model we aim to develop novel therapeutic strategies for the treatment of patients. Finally, we want to identify endocrine disruptors that directly or indirectly interfere with TH transporter functions thereby compromising tissue-specific TH homeostasis.

Another research focus of our group comprises the anti-aging hormone klotho. Klotho deficient mice develop various symptoms of premature aging and show a very short life-span. By analysing tissue-specific klotho knockout mice we want to define the role of klotho in brain aging and to assess its role within the neuroendocrine system.

tl_files/bilder/AG Bilder/AG Heuer/Cerebellaren Purkinje Zelle_AG Heuer.jpg

Cerebellar Purkinje cell development is highly dependent on proper TH supply and can be monitored in organotypic slice cultures after transfection with a GFP reporter construct.

Selected projects

1. Physiological functions of thyroid hormone transporters

Our group is interested in determining the (patho-) physiological functions of TH transporters during brain development and aging. We are particularly experienced in analyzing mouse models that are deficient in specific thyroid hormone transporters in certain cell types or tissues (project funded by DFG and embedded in SPP1629). Using in vitro as well as in vivo approaches, we further aim to identify chemicals that exert e.g. neurotoxic actions by blocking TH transport into the brain. For these studies, we apply a variety of techniques such as in situ hybridization, immunohistochemistry, molecular biology, and primary cell cultures.

tl_files/bilder/AG Bilder/AG Heuer/Expression Mct8_AG Heuer.jpg
Localization of the thyroid hormone transporter Mct8 in the mouse brain - Illustration of Mct8 expression in the CNS by in situ hybridization (left) and immunohistochemistry (right). NeuN is a marker for post-mitotic neurons.

2. Allan-Herndon-Dudley Syndrome: mechanisms of disease and evaluation of therapeutic approaches

Patients carrying inactivating mutations in the gene encoding the thyroid hormone transporter MCT8 (SLC16a2) suffer from a severe form of psychomotor retardation and abnormal TH concentrations in the circulation (Allan-Herndon-Dudley syndrome). For studying the pathogenic mechanisms we recently developed a mouse model (Mct8/Oatp1c1 dko mice) that fully replicates the patients´ phenotype and is therefore suited for testing therapeutic approaches. By taking advantage of these animals we are currently studying the therapeutic capacity of TH analogs such as Triac that can exert thyromimetic actions in the brain but are not dependent on MCT8 for cellular entry. This project is funded by the BMBF and carried out in collaboration with Prof. J. Bernal (Spain) and Dr. L. Appelbaum (Israel) as partners in the E-RARE consortium "THYRONERVE".

Selected publications

Mayerl S, Müller J, Bauer R, Richert S, Kassmann CM, Darras VM, Buder K, Boelen A, Visser TJ, Heuer, H: Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis. J Clin Invest 124(5): 1987-1999, 2014. [pubmed] (open access)

Müller J, Mayerl S, Visser TJ, Darras VM, Boelen A, Frappart L, Mariotta L, Verrey F, Heuer H: Tissue-specficic alterations in thyroid hormone homeostasis in combined Mct8 and Mct10 deficiency. Endocrinology 155: 315-325, 2014. [pubmed] (open access)

Kersseboom S*, Horn S*, Visser WE, Chen J, Friesema EC, Vaurs-Barrière C, Peeters RP, Heuer H#, Visser TJ#: In vitro and mouse studies support therapeutic utility of triiodothyroacetic acid in MCT8 deficiency. Molecular Endocrinology 28: 1961-1970, 2014. (*,# equal contribution) [pubmed]

Groba C, Mayerl S, van Mullem AA, Visser TJ, Darras VM, Habenicht A J, Heuer H: Hypothyroidism compromises leptin production and hypothalamic leptin signaling in mice. Molecular Endocrinology 27: 586-597, 2013. [pubmed] (open access)

Trajkovic M, Visser TJ, Mittag J, Horn S, Lukas J, Darras VM, Raivich G, Bauer K, Heuer H: Abnormal thyroid hormone metabolism in mice lacking the monocarboxylate transporter 8. J Clin Invest 117: 627-635, 2007. [pubmed] (open access)