Most primate species have a relatively large brain with a surface marked by pronounced bulges and furrows. This is not the case with common marmosets (Callithrix jacchus). The brains of these small monkeys are smooth and virtually unfolded. Researchers at the German Primate Center (DPZ) —the Leibniz Institute for Primate Research in Göttingen have investigated, in a recent study, which cellular processes during embryonic development cause the marmoset brain to develop differently from a certain stage onward. In experiments with brain organoids, they were able to show that certain neural progenitor cells—from which neurons arise—develop differently in marmosets, both morphologically and temporally. Several processes occurring at different levels and involving various types of progenitor cells govern this phenomenon, which ultimately leads to a reduction in the size and folding of the marmoset brain. The study sheds new light on the evolutionary development of the primate brain and could help improve our understanding of developmental disorders in the human brain in the future (Science Advances).
Its size and degree of folding are the defining characteristics of the brains of many primates. In particular, the walnut-like grooves and ridges of the human brain vastly increase its surface area and provide space for billions of nerve cells. This enables complex thought processes and makes the human brain exceptionally powerful. Researchers now believe that even the common ancestor of all primates had a medium-sized and at least partially folded brain.
However, this is not the case for some primate species living today. Common marmosets (Callithrix jacchus), a South American primate species increasingly used in biomedical research, have a smooth and nearly unfolded brain surface. Researchers at the German Primate Center have investigated how this comes about.
"We wanted to understand which changes at the cellular level cause the marmoset brain to grow less and form fewer folds," explains Lidiia Tynianskaia, one of the study's two first authors and a PhD student in the Junior Research Group Brain Development and Evolution at the DPZ. "At the beginning of development, the common marmoset brain exhibits the typical structure and composition of a large, folded primate brain. As development progresses, processes must therefore occur that effectively slow down the production of nerve cells."
Neural progenitor cells develop differently
In comparative experiments using brain organoids from common marmosets and humans, the scientists focused in particular on the brain's progenitor cells, as these are responsible for the production of neurons. The number of neurons is one of the decisive factors in determining how large and how heavily folded a brain becomes.
The researchers found that several processes occurring at different levels and in different cell types lead to a reduction in the size and folding of the cerebral cortex in marmosets.
"Our investigations have shown that certain progenitor cells in the common marmoset divide significantly more slowly than in humans," explains César Mateo Bastidas Betancourt, also a first author of the study and a PhD student in the Junior Research Group. "Other progenitor cells have a simpler structure than their human counterparts, with fewer processes, and are therefore less proliferative. Both of these factors ultimately result in fewer nerve cells, which contributes to a smaller size and less folding of the cerebral cortex in marmosets."
In addition, the scientists were able to show that the timing of certain characteristics and behaviors of the progenitor cells in marmosets is altered compared to humans. As a result, the common marmoset's progenitor cells have a shorter overall time window during which they can proliferate rapidly.
Brain organoids provide crucial insights
Most of the experiments were conducted in brain organoids. These small three-dimensional cell structures accurately reflect the timing of certain developmental stages of the brain. "The study combines the advantages of in vivo and in vitro methods," says Michael Heide, head of the Junior Research Group Brain Development and Evolution. "Organoids are well-suited for obtaining statistically robust results because such sample sizes are not feasible in primates. We subsequently repeated some key experiments in fetal brain tissue to confirm the results from the organoids."
This revealed that 50-day-old marmoset organoids closely resemble natural brain development on day 90. This comparison was important because it was the only way for the researchers to accurately align the timing of development in organoids with that in the marmoset brain and reliably interpret the results.
The study highlights how the diversity of brain sizes and shapes in primates could have evolved and, at the same time, provides an important framework for better understanding developmental processes and their disruptions in the human brain.
