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UNDERSTANDING BRAIN WRINKELS: Study sheds light on major question in brain development – how the distinctive folds in the cortex, seen in humans, whales, and some other animals, form.
MULTIPLE INFLUENCES: Genetic changes that reduced how strongly brain cells stick together, combined with an increase in their number, triggered dramatic folding in the normally smooth mouse brain.
PINPOINTING THE ROLES OF DIFFERENT CELLS: Boosting different types of early-stage neurons influenced fold shape, leading to either grooves (sulci) or ridges (gyri).
GUIDING FUTURE RESEARCH: The results show how cell behaviour and number shape the developing brain, offering clues to evolution, function, and disease.
One of the defining features of humans is our brain’s remarkable capacity for language, planning, memory, creativity, and more. These abilities stem not just from our large brain size, but also from the folded structure of the brain’s outer layer, the cerebral cortex. A new study offers insight into how these wrinkles form, pointing to a range of contributing factors – including the number of early-stage brain cells, how they migrate during development, and the specific types of cells involved. These findings may help guide future research into brain development, evolution, and health.
One of the brain’s biggest mysteries
Unlike most animals, whose brains are smooth, some larger species – including humans, some other primates, whales, dolphins, and pigs – have a wrinkled cerebral cortex, featuring grooves (sulci) and ridges (gyri) on the surface. This distinctive structure substantially increases the brain’s surface area and is associated with a wide range of higher cognitive functions. Yet, while these folds appear to offer clear evolutionary advantages, how they form remains one of the biggest mysteries in brain development.
Previous work by Rüdiger Klein’s team at the Max Planck Institute for Biological Intelligence showed that removing genes for two adhesion molecules that help neurons migrate together changes how brain cells move around in the developing mouse brain. Without these molecules, neurons spread out more widely, causing the normally smooth mouse cortex to form grooves, similar to those seen in the folded human brain.
The new study, published in Nature Communications , builds on this work, introducing additional genetic changes that simultaneously increased the number of progenitor cells – the early cells that give rise to neurons. When combined, these changes led to even more extensive folding than the team observed in their previous study, with complex patterns of grooves and ridges emerging in the cortex. Using genetics approaches, the researchers also found that boosting the numbers of different progenitor cells specifically influenced whether grooves or ridges formed.
Combined impacts shaping the cortex
“It’s thought that our brain’s wrinkles form through a mix of rapid cell growth and the movement of neurons as the brain develops,” says Seung Hee Chun, a postdoctoral researcher and first author of the study. “But how these processes work together to create the brain’s characteristic grooves and ridges was not well known. Our study suggests that cell movement, how tightly neurons migrate together, and how densely they are packed all contribute. It’s the combination of these factors – rather than any one alone – that drives things.”
To carry out the study, the researchers used a combination of conditional genetic mouse models, single-cell sequencing, and computer simulations. Interestingly, the findings also suggest that the type of neural progenitor cell plays a role in shaping wrinkles. For example, boosting intermediate progenitors favoured the formation of sulci. In contrast, increasing apical progenitors – another specific group of early-stage neurons - led to the formation of gyri.
“These findings open the door to exploring how other cellular, genetic and mechanical factors might influence cortex development,” says Rüdiger Klein, Director at the Max Planck Institute for Biological Intelligence. “Even between humans, the folding patterns of the cortex can vary greatly from person to person. Understanding what drives these differences could help us better learn how the brain develops, and how its shape relates to aspects such as function, evolution, behavior, and health.”
Prof. Dr. Rüdiger Klein
Director
MPI for Biological Intelligence
ruediger.klein@bi.mpg.de
Cortex Folding by Combined Progenitor Expansion and Adhesion-Controlled Neuronal Migration
Seung Hee Chun, Da Eun Yoon, D. Santiago Diaz Almeida, Mihail Ivilinov Todorov, Tobias Straub, Tobias Ruff, Wei Shao, Jianjun Yang, Gönül Seyit-Bremer, Yi-Ru Shen, Ali Ertürk, Daniel del Toro, Songhai Shi, and Rüdiger Klein
Nature Communications, online 28 August 2025
https://www.bi.mpg.de/klein - Department website
How do wrinkles form in the brain? Researchers compared brain sections of mice with different geneti ...
Copyright: © MPI for Biological Intelligence / Seung Hee Chun
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How do wrinkles form in the brain? Researchers compared brain sections of mice with different geneti ...
Copyright: © MPI for Biological Intelligence / Seung Hee Chun
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