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Researchers around the world are studying how the human brain achieves its extraordinary complexity. A team at the Central Institute of Mental Health in Mannheim and the German Primate Center – Leibniz Institute for Primate Research in Göttingen has now used organoids to show that the ARHGAP11A gene plays a crucial role in brain development. If this gene is missing, key processes involved in cell division and structure become unbalanced.
The human brain distinguishes us from other living beings like no other organ. It enables language, abstract thinking, complex social behavior, and culture. But how can this extraordinarily powerful organ develop, and how is it ensured that nerve cells and supporting cells form in exactly the right places to create the complexity of the human brain? A team led by Dr. Julia Ladewig at the Central Institute of Mental Health (CIMH) in Mannheim and Dr. Michael Heide at the German Primate Center (DPZ) in Göttingen has investigated this question at the molecular level. In a study now published in the journal Cell Reports, the researchers show that the ARHGAP11A gene plays a key role in organizing brain development.
Order in the stem cell bank: Researchers discover central role of ARHGAP11A
Deep within the developing brain lies the ventricular zone. This can be described as a stem cell reservoir, as specialized stem cells there continuously produce new nerve cells. In order for these cells to know how to divide, where to migrate, and when to develop into nerve cells, they must constantly remodel their internal framework, the cytoskeleton. Researchers have now discovered that the ARHGAP11A gene plays a key role in controlling these processes. It ensures that the stem cells maintain their orientation during cell division and that the architecture of the ventricular zone remains stable.
When orientation is lost
Without ARHGAP11A, stem cells lose their order, detach from the tissue too early, and begin to transform into nerve cells. This leads to the stem cell reservoir being depleted too quickly. As a result, important cell types are later lacking, such as support cells, which are essential for the maturation and stability of the brain.
The ARHGAP11A protein acts like a molecular switch. It regulates so-called Rho GTPases, small molecules that control the cytoskeleton and thus determine how cells form, divide, and move. In this way, ARHGAP11A ensures that precursor cells retain their shape and arrange themselves correctly in the ventricular zone.
Brain organoids provide crucial insights
To investigate these mechanisms in detail, the researchers used brain organoids, i.e., models of the human cerebrum grown from stem cells in the laboratory. This enabled them to understand how ARHGAP11A shapes cell architecture and how a disruption of this mechanism causes malformations. Remarkably, the researchers were able to show that short-term pharmacological inhibition of the overactive signaling pathways partially reverses the malformation. “This shows that this developmental process of the brain can in principle be influenced,” explains first author Yannick Hass, a researcher at the Hector Institute for Translational Brain Research (HITBR) and at the CIMH in Mannheim.
Unmatched precision through brain organoids
The study shows that studies in mice cannot fully replicate the complexity of human brain development. “The same effects could not be detected in mouse tissue after the loss of ARHGAP11A. This underscores how important human organoid models have become for biomedical research,” says Dr. Michal Heide, head of the Brain Development and Evolution working group at the German Primate Center.
Dr. Julia Ladewig, head of the Developmental Brain Pathologies Research Group at the CIMH, also emphasizes the importance of this approach: “Brain organoids give us the opportunity to study the development of the human brain with unprecedented precision. This allows us to better understand its evolutionary characteristics and gain new insights into developmental disorders and psychiatric diseases.”
Enabling new diagnostic and therapeutic approaches
In the long term, the research should help to better understand genetic risk factors for neurodevelopmental disorders. These include microcephaly, in which the brain remains unusually small, and neuronal heterotopias, in which nerve cells migrate to the wrong places during brain development. The knowledge gained can form the basis for new diagnostic and therapeutic approaches, thereby contributing to the long-term improvement of treatment for such rare diseases.
About CIMH
The Central Institute of Mental Health (CIMH) stands for internationally outstanding research and pioneering treatment concepts in psychiatry and psychotherapy, child and adolescent psychiatry, psychosomatics and addiction medicine. The CIMH clinics provide psychiatric care for the population of Mannheim. At the CIMH, mentally ill people of all ages can rely on the most advanced treatments based on international standards of knowledge. Educating people about mental illness, creating understanding for those affected and strengthening prevention is another important part of our work. In psychiatric research, the CIMH is one of the leading institutions in Europe. Since 2021, it has been a site of the German Centre for Mental Health. The CIMH is institutionally linked to Heidelberg University through jointly appointed professors from the Mannheim Medical Faculty. The CIMH is a member of the Health + Life Science Alliance Heidelberg Mannheim.
About HITBR
The Hector Institute for Translational Brain Research (HITBR) was founded as a joint project of the Central Institute of Mental Health (CIMH), the German Cancer Research Center (DKFZ) and the Hector Foundation II. The aim of HITBR is to identify new molecular and functional targets for the therapy of severe psychiatric diseases and brain tumours.
About the German Primate Center
The German Primate Center GmbH (DPZ) – Leibniz Institute for Primate Research conducts biological and biomedical research on and with primates in the fields of infectious disease research, neuroscience, and primate biology. The DPZ also maintains field stations in the tropics and is a reference and service center for all aspects of primate research. The DPZ is one of 96 research and infrastructure facilities of the Leibniz Association.
Dr. Julia Ladewig
Hector Institute for Translational Brain Research (HITBR)
Central Institute of Mental Health
E-Mail: julia.ladewig@zi-mannheim.de
Dr. Michael Heide
German Primate Center
Phone: +49 551-3851-323
Email: mheide@dpz.eu
Hass, Y, Kniep, J, Hoffrichter, A, Marsoner, F, Eşiyok, N, Gasparotto, M, Pio Loco detto Gava, M, Artioli, A, Guida, C, Meuth, S G, Huttner, W B, Jabali, A, Heide, M and Ladewig, J (2025): ARHGAP11A Maintains Cortical Progenitor Identity Through RHOA–ROCK Signalling During Human Brain Development. Cell Reports, Volume 44, Issue 12, 116599, https://www.cell.com/cell-reports/fulltext/S2211-1247(25)01371-3
https://medien.dpz.eu/pinaccess/showpin.do?pinCode=v1D7e0q5a2k4 Printable images can be found at this link
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