Günther Schütz and the regulation of gene expression by nuclear receptors
Professor Dr. Günther Schütz’s work on the cell- and development-specific gene regulation using nuclear receptors has led, amongst other things, to new insights into the steroid hormone-dependent early development and differentiation of the nervous system, the molecular mechanisms of learning and the development and regulation of drug addiction. Schütz has now been appointed Helmholtz professor, which will enable him to continue his work beyond retirement age.
“German research cannot afford to be without creative, motivated people who want to continue their work on strategically important topics,” said Professor Dr. Otmar Wiestler, Scientific Director of the German Cancer Research Centre (DKFZ) commenting on the appointment of Günther Schütz and Werner Franke, two internationally renowned DKFZ scientists, as Helmholtz professors.
The new funding instrument of the Helmholtz Society of German Research Centres enables outstanding scientists to continue working as senior researchers and lead their research groups for (initially) three years after the official retirement age. “Since 1st May 2008 when I was appointed Helmholtz professor, things have stayed pretty much the same as they were before the appointment,” said Schütz. “I have my co-workers, am still working in exciting areas of research, I still cycle to work and I do all I can to acquire third-party funding.”
Schütz’s major field of research focuses on the regulation of genes through steroid hormones. The receptors of these hormones, in contrast to the receptors of polypeptide hormones and growth factors, are not located on the cell membrane, but inside the cell. They are members of the big protein super family of “nuclear receptors” (NRs), which also includes vitamin D receptors, thyroid hormone receptors (e.g, thyroxin) and retinoic acid (vitamin A) receptors. In addition, there is a number of nuclear “orphan receptors” which are constitutive, which means that they are effective without ligands or that no specific ligands have so far been identified.
NRs have important functions in the regulation of growth and the differentiation of cells and tissue. They exert their effect on the transcription level, i.e. the cell- and development-specific activation or inactivation of genes, and thus represent a direct connection from signalling molecules on the outside and the regulatory DNAsequences inside the cell that are necessary for transcription. Schütz has dealt with a broad range of these gene regulation proteins, and has numerous publications in prestigious journals such as Cell, Neuron, Nature, Science, PNAS or EMBO Journal. Schütz and his co-workers have worked intensively on adrenal cortical hormones (glucocorticoids and mineralocorticoids) and on oestrogen (oestradiol)-dependent signalling chains. The receptors of the corticosteroid hormones, which regulate the carbohydrate and protein metabolisms as well as the salt metabolism, are closely related to the sex hormone oestradiol; they recognise on the DNA similar, but different specific regulatory sequences. In addition, they exert their effect by way of protein-protein interactions that do not involve DNA binding.
Günther Schütz studied human medicine at the Universities of Frankfurt, Berne and Gießen and did his doctorate at the Institute of Physiological Chemistry at the University of Marburg. After working as a medical assistant at the Free University (FU) in Berlin, he became a post-doctoral fellow, and later assistant professor, at the Institute of Cancer Research at Columbia University, New York, posts that were financed with grants from the DFG and the Fulbright Commission. After six years in New York, he moved on to become head of a research group at the Max Planck Institute for Molecular Genetics in Berlin, where he stayed from 1975 until 1980. He habilitated in physiological chemistry at the FU Berlin and in 1980 accepted a call to the German Cancer Research Centre as the head of the “Molecular Biology of the Cell I” department. Schütz, who is also professor of molecular biology at the Life Sciences Faculty of the University of Heidelberg, has received many prizes, including the German Research Foundation Gottfried Wilhelm Leibniz Award (1987), the European Medal of the Society of Endocrinology (1997) and the Max Planck Research Prize for International Cooperation (1998). He is a member of several international academies and scientific associations: he is an elected member of the “Academia Europaea” (London), an active member of the American Association for Cancer Research (AACR) and is also a member of the German Academy of Sciences Leopoldina in Halle/Saale (Genetics/Molecular Biology and Cell Biology division).
Gene targeting in adult mice
Schütz and his co-workers used “gene targeting” in mice to characterise the function of steroid hormone receptors. Gene targeting is a recombination method that enables researchers to create specific mutations in the targetgenes. The complete silencing of the entire gene in the entire animal (knockout mice) is only of limited value for the analysis of hormone-dependent differentiations, explains Schütz citing the importance of glucocorticoid receptor function for maturation processes in the lung. Knockout mice that do not have glucocorticoid receptors die in the early stages of development. The introduction of mutations into the lung epithelium using the Cre/LoxP system lets the mice return to a virtually normal state. However, if the glucocorticoid receptors in the lung mesenchymal cells are switched off, then all the animals will die. This finding is surprising because it had previously been assumed that lung epithelial cells are controlled by glucocorticoids.
Schütz and his team also use the Cre/LoxP system to analyse the hormone-dependent functions and differentiations in the brain. For example, adult mice whose corticosteroid receptor genes are switched off in the respective neurons, are being examined for their behaviour, synaptic plasticity, activity of the stress axis and the neurogenesis of the hippocampus. The researchers have been able to show that the neurons of the gonadotropin releasing hormone (GnRH) in the hypothalamus, which are key regulators of mammalian fertility, are under the control of the oestradiol receptor; however, this receptor does not have a direct effect, but mediates its signal by way of kisspeptin, a ligand for the G-protein coupled receptor 54 (GPR54), key to human development during puberty. In a new paper – published with scientists from the Central Institute of Mental Health in Mannheim and the University of Geneva – Schütz and his team investigated how the glutamate receptors in dopamine-specific neurons control the process of “drug-mediated synaptic plasticity” during the development and continuation of cocaine addiction. These and other important investigations, including work on the orphan nuclear receptor 'tailless' will be described in greater detail in a separate article.