Prof. Dr. med. Günther Schütz

The glucocorticoid receptor modulates transcription by different modes of action

Our laboratory is studying the role of nuclear receptors during normal development and disease. Since germline-inactivation of the mineralocorticoid receptor (MR) or the glucocorticoid receptor (GR) gene results in early lethality, we generated mutant mice with neuron-specifc inactivation of either gene in the forebrain. To avoid effects on brain development we established a transgenic mouse line that allows inducible gene inactivation in adult forebrain neurons.
The subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus (DG) are the largest germinal zones of sustained neurogenesis during adulthood. We found that the orphan nuclear receptor tailless (Tlx) is exclusively expressed in these slowly dividing neural stem cells (NSCs). We found that overexpression of Tlx induced expansion of the neural stem cell population in mice. These cells initiate the development of glioma-like lesions and gliomas. Glioma development is accelerated upon loss of the tumor suppressor p53 in adult neural stem cells. Therefore our goal is to generate transgenic mouse models that will allow for elucidation of the molecular mechanisms involved in disease development.
In a novel project we study the function of microRNAs in adult neural stem cells and neurons, their impact on neural plasticity and their involvement in the CNS control of energy balance and metabolism.

The major aims in our future work will be:
- genome-wide identification of binding sites of the mineralo- and glucocorticoid receptor in the hippocampus
- characterization of Tlx target genes in the suvbentricular zone and the subgranular zone by ChIP-Seq methodology.
With this method we will identify the regulatory sequences that cause spatial and temporal expression of the target genes of these nuclear receptors. We anticipate that with these approaches, chromatin immunoprecipitation coupled to massively parallel sequencing, the characterization of target genes for these nuclear receptors (GR, MR and Tlx) will be possible. These efforts thus will lead to a molecular understanding of the action of these regulatory factors.