Actin enhances the action of sex hormones

Steroid hormones, including sex hormones such as estrogen or testosterone, are important signaling molecules responsible for controlling differences in male and female phenotypes. They work by attaching to receptor molecules that turn hormone-dependent gene activity on and off.

Researchers from the University of Freiburg and Kiel University Hospital have found that components of the cytoskeleton play an important role in this process. These results are relevant to disease diagnosis and the study of diseases and cancers in which steroid hormones play an important role. The study  was published in the prestigious journal Nature

Recent studies have shown that filamentous actin, a component of the cytoskeleton, directly interacts with androgen receptors in the nucleus and enhances their activity. Androgen receptors mediate sex hormone signaling for male sex development, but also contribute to the development of prostate cancer.

Genetic variation is the main indicator

Scientists with different research priorities from Freiburg, Kiel and Lübeck jointly carried out this interdisciplinary research. The project is developed by professors and doctors. Robert Gross and Dr. PD. Nadine Hornig: Groß Freiburg conducts research at the CIBSS Center for Integrated Biosignaling Research and the Department of Medicine at the University of Kiel.

While studying cells with androgen insensitivity syndrome (AIS), researchers began to understand the previously unknown relationship between the hormones actin and steroids. People with AIS have a male XY chromosome, but males and even females are rare. This is usually due to an alteration of the androgen receptor, meaning the male hormone is inactive. However, the androgen receptor is usually unchanged in AIS patients.

“We wanted to understand the genetic changes that caused AIS in these patients,” Hornig said. “So we wanted to identify other molecules that play a role in the development of sex characteristics.” To do this, the researchers used a screening method to study cells with AIS. They found mutations in the DAAM2 gene in two patients: The molecule belongs to the formin class and controls the synthesis and dynamic elongation of actin filaments. As part of the cytoskeleton, actin is important for cell stability and motility, but it also has regulatory functions.

High-resolution microscopy can visualize processes in the nucleus

The researchers used high-resolution 3D SIM microscopy to investigate whether DAAM2 is important for its effects on sex hormones. This is a sophisticated technique that can be used to observe the movement of molecules within a cell. The images show that DAAM2 and actin co-localize directly with the androgen receptor in the nucleus. Further experiments showed that this centralization is important for the control of gene activity.

“This is an unknown mode of action and we were able to characterize a very important receptor here,” Gross said, emphasizing the significance of the new discovery. The team suggests that this mechanism may be general and may also affect the action of other steroid hormones. “It may play a role in many physiological and disease processes,” explains Gross. “It will be interesting to see if it opens up new treatments.”

Patients with AIS are more likely to be diagnosed

This finding also provides the basis for further research into the development of sex characteristics, which will allow more patients with AIS to be diagnosed more accurately: “Previously insensitive patients with androgens, but without the altered androgen receptors, not getting obvious symptoms…, obviously.. despite the pain,” says Hornig. “We can now make an accurate diagnosis for people with altered DAAM2.”