Components of Cytoskeleton Strengthen Effect of Sex Hormones

Steroid hormones, to which belong sex hormones like estrogen or testosterone, are important signaling molecules and are responsible among other things for controlling female and male phenotypic sex differentiation. They act by binding to receptor molecules that switch on and off the activity of hormone-dependent genes. Researchers at the University of Freiburg and Kiel University Hospital have discovered that components of the cytoskeleton are critically involved in this process. The findings are relevant for the diagnosis of medical conditions and the study of diseases and cancers in which steroid hormones play important roles. The study was published in the renowned journal Nature.

The new research findings show that filamentous actin, a component of the cytoskeleton, interacts with the androgen receptor directly in the cell nucleus and strengthens its effect. The androgen receptor mediates the signals of sex hormones for male sex development but also promotes the progression of prostate cancer.

A genetic modification as the key indicator

Scientists with different research foci from Freiburg, Kiel, and Lübeck collaborated on the study across disciplines. The project was led jointly by Prof. Dr. Robert Grosse and PD Dr. Nadine Hornig: Grosse conducts his research at the Cluster of Excellence CIBSS – Centre for Integrative Biological Signalling Studies and the University of Freiburg’s Faculty of Medicine, Hornig at University of Kiel´s Faculty of Medicine and the University Hospital Schleswig-Holstein, campus Kiel.

The researchers became aware of the previously unknown connection between actin and steroid hormones while studying the cells of patients with a so-called androgen insensitivity syndrome (AIS). People who live with AIS have a set of male XY chromosomes but have less pronounced male sexual characteristics, extending even to a completely female appearance. This is often due to a change in the androgen receptor, which means that male sex hormones can no longer take effect. However, the androgen receptor is frequently unchanged in patients with AIS.

“We want to find out what genetic modifications cause AIS in these patients,” explains Hornig. “Thus, we wanted to identify further molecules that play a role in the development of sexual characteristics.” For this purpose, the researchers used a screening method to examine the cells of patients with AIS. In the process, they discovered mutations in the DAAM2 gene in two patients: The molecule belongs to the group of formins and controls the dynamic polymerization and elongation of actin filaments. As a part of the cytoskeleton, actin is important for the stability and locomotion of cells but also serves regulatory functions.

High-resolution microscopy reveals the processes in the cell nucleus

The researchers used high-resolution 3D SIM microscopy to examine whether DAAM2 is indeed important for the effect of sex hormones. This is an elaborate technique that can be used to observe molecular movements within cells. The images show that DAAM2 and actin colocalize with the androgen receptor directly in the cell nucleus. Further experiments demonstrated that this colocalization is important for the control of gene activity.

“This is a completely unknown mode of action, which we succeeded in describing here for a very important receptor,” says Grosse, highlighting the significance of the new findings. The research team assumes that the mechanism could be widespread and also influences the effect of other steroid hormones. “This could play a role in many physiological processes and diseases. It will be exciting to see whether it will enable new therapeutic approaches,” explains Grosse.

Diagnosis possible for more patients with AIS

The discovery also provides a basis for further research on the development of sexual characteristics and enables a clear diagnosis for more patients with AIS: “Previously, patients with androgen insensitivity but without a modification in the androgen receptor did not receive a clear diagnosis despite having clear symptoms,” says Hornig. “Now we can make a clear diagnosis for those in whom DAAM2 is altered.“

About the Cluster of Excellence CIBSS

The Cluster of Excellence CIBSS – Centre for Integrative Biological Signalling Studies – has the goal of reaching a comprehensive understanding of biological signaling processes across scales – from interactions between individual molecules and cells to processes in organs and entire organisms. The knowledge thus obtained can be used to control signals in a targeted manner. This in turn enables the researchers not only to gain insights in research but also to develop innovations in medicine and plant sciences. www.cibss.uni-freiburg.de

Fact sheet:

• Original publication: Julian Knerr, Ralf Werner, Carsten Schwan, Hong Wang, Peter Gebhardt, Helga Grötsch Almuth Caliebe, Malte Spielmann, Paul-Martin Holterhus, Robert Grosse, Nadine C. Hornig (2023): Formin-mediated nuclear actin assembly at androgen receptors promotes transcriptional droplet formation. In: Nature. DOI: 10.1038/s41586-023-05981-1
• Robert Grosse is professor of pharmacology and toxicology at the faculty of medicine and Cluster of Excellence CIBSS at the University of Freiburg and director of Division I of the Institute of Experimental and Clinical Pharmacology and Toxicology at the University of Freiburg. His research focus is the regulation of actin and its role in the maintenance of health and in diseases. He also uses high-resolution imaging methods for this purpose.
• Nadine Hornig is a research group leader at the Institute of Human Genetics of the University Hospital Schleswig-Holstein in Kiel and works in the area of pediatric endocrinology and human genetics. Her research focus is the role of cofactors of the androgen receptor in the development of androgen resistance.
• The study was funded by the German Research Foundation (DFG).

Caption:

Super-high-resolution microscopic image of a cell that has been exposed to the sex hormone dihydrotestosterone. The androgen receptor (violet) and actin (green) are visible in the cell nucleus. Both molecules are stained with fluorescent dyes and thus made visible. The individual structures made visible (right) are only 200 nanometers (200 millionths of a millimeter) small. Image and Video: Julian Knerr/University of Freiburg

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Contact:
Annette Kollefrath-Persch
University and Science Communications
University of Freiburg
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