Unlocking Human Brain Evolution

Summary: Researchers made a significant discovery in the study of human brain evolution, identifying epiregulin as a key factor in the expansion of the human neocortex. By comparing brain development between mice and humans and utilizing 3D brain organoids, the team found that epiregulin promotes the division and expansion of stem cells, crucial for neocortex development.

This study, which utilized cutting-edge 3D culture technology, suggests that the quantity of epiregulin, rather than its presence or absence, distinguishes human brain development from that of other species, including primates like gorillas. The research offers new insights into what makes the human brain unique and underscores the value of innovative methodologies in understanding complex evolutionary processes.

Key Facts:

  1. Epiregulin’s Role in Brain Expansion: Epiregulin promotes the expansion of stem cells in the developing brain, contributing to the complexity and size of the human neocortex.
  2. 3D Brain Organoids as a Research Tool: The study leveraged 3D brain organoids to mimic human brain development, enabling a deep dive into the cellular mechanics without invasive methods.
  3. Quantity Over Presence: The research indicates that humans and other primates, including gorillas, possess the epiregulin gene, but the level of its expression in humans is key to our neocortex development.

Source: TUD

What makes us human? According to neurobiologists it is our neocortex. This outer layer of the brain is rich in neurons and lets us do abstract thinking, create art, and speak complex languages.

An international team led by Dr. Mareike Albert at the Center for Regenerative Therapies Dresden (CRTD) of TUD Dresden University of Technology has identified a new factor that might have contributed to neocortex expansion in humans.

The results were published in the EMBO Journal.

This shows brain models.
Comparing the effect of epiregulin in human and gorilla brain organoids, the team found that adding epiregulin to gorilla brain organoids can further promote the expansion of stem cells. Credit: Neuroscience News

The neocortex is the characteristic folded outer layer of the brain that resembles a walnut. It is responsible for higher cognitive functions such as abstract thinking, art, and language.

“The neocortex is the most recently evolved part of the brain,” says Dr. Mareike Albert, research group leader at the CRTD.

“All mammals have a neocortex, but it varies in size and complexity. Human and primate neocortices have folds while, for example, mice have a completely smooth neocortex, without any creases.”

The folds characteristic of the human brain increase the surface area of the neocortex. The human neocortex has a greater number of neurons that support complex cognitive functions.

The molecular mechanisms driving neocortex evolution are still largely unknown. “Which genes are responsible for inter-species differences in neocortex size? What factors have contributed to brain expansion in humans? Answering these questions is crucial to understanding human brain development and potentially addressing mental health disorders,” explains Dr. Albert.

The Power of Brain Organoids

To search for factors influencing brain expansion, the Albert group compared developing brains of mice and humans.

“Stem cells in mice don’t divide as much and don’t produce as many neurons compared to primates. Humans, on the other hand, have a large number of stem cells in the developing brain. This highly expanded pool of stem cells underlies the increase in number of neurons and brain size,” explains Dr. Albert.

The team found a factor that is present in humans but not in mice. Using 3D cell culture technology, the group tested if the newly identified factor could influence the expansion of the neocortex.

“Thanks to the research awarded with the Nobel prize in 2012, it is possible to turn any cell into a stem cell. Such a stem cell can then be transformed into a three-dimensional tissue that resembles an organ, e.g., a brain. Human stem cells make it possible to study development and diseases directly in human tissues,” explains Dr. Albert.

These 3D brain cultures, or brain organoids, may not resemble brains to an untrained eye, but they mimic the cellular complexity of developing brains. “Most of the cell types of the developing brain are present. They interact, signal, and are similarly arranged as in an actual human brain,” says Dr. Albert.

Using 3D brain organoids, the group was able to show that a growth factor, known as epiregulin, indeed promotes the division and expansion of stem cells in the developing brain.

All About the Amount

“Knowing that epiregulin drives expansion of human neocortical stem cells, we looked back at the gene that codes for epiregulin and tried to trace it through the evolutionary tree,” says study lead author Paula Cubillos, a doctoral candidate at the CRTD. The gene is not unique to humans, but also present in other primates and even in mice.

“Epiregulin is not produced in the developing mouse brain, however, because the gene is permanently shut off and not being used. We were intrigued to understand whether there are any differences in how epiregulin works in humans and other primates,” explains Paula Cubillos.

The researchers turned again to the 3D culture technology. Using gorilla stem cells, the researchers generated gorilla brain organoids. “Gorillas are endangered species. We know very little about their brain development. Organoids made from stem cells offer a way to study their brain development without interacting with the species at all,” says Dr. Albert.

Comparing the effect of epiregulin in human and gorilla brain organoids, the team found that adding epiregulin to gorilla brain organoids can further promote the expansion of stem cells. However, adding even more epiregulin to human brain organoids did not have the same effect. This might be because the human neocortex has already expanded to a very large extent.

“Unlike previously identified factors, epiregulin as such seems not to be unique to humans. Instead, the amount of the growth factor seems to be the crucial regulator for the inter-species differences,” concludes Dr. Albert.

This study not only advances our understanding of human uniqueness but also highlights the importance of new technologies that offer ethical and non-invasive complements to animal research.

The study was performed in collaboration with King’s College London, the Medical Faculty Carl Gustav Carus of TU Dresden, the Max Planck Institute of Molecular Cell Biology and Genetics, and Hannover Medical School.

About this neuroscience and evolution research news

Author: Magdalena Gonciarz
Source: TUD
Contact:Magdalena Gonciarz – TUD
Image: The image is credited to Neuroscience News

Original Research: Open access.
The growth factor EPIREGULIN promotes basal progenitor proliferation in the developing neocortex” by Mareike Albert et al. EMBO Journal


The growth factor EPIREGULIN promotes basal progenitor proliferation in the developing neocortex

Neocortex expansion during evolution is linked to higher numbers of neurons, which are thought to result from increased proliferative capacity and neurogenic potential of basal progenitor cells during development.

Here, we show that EREG, encoding the growth factor EPIREGULIN, is expressed in the human developing neocortex and in gorilla cerebral organoids, but not in the mouse neocortex. Addition of EPIREGULIN to the mouse neocortex increases proliferation of basal progenitor cells, whereas EREG ablation in human cortical organoids reduces proliferation in the subventricular zone.

Treatment of cortical organoids with EPIREGULIN promotes a further increase in proliferation of gorilla but not of human basal progenitor cells. EPIREGULIN competes with the epidermal growth factor (EGF) to promote proliferation, and inhibition of the EGF receptor abrogates the EPIREGULIN-mediated increase in basal progenitor cells.

Finally, we identify putative cis-regulatory elements that may contribute to the observed inter-species differences in EREG expression.

Our findings suggest that species-specific regulation of EPIREGULIN expression may contribute to the increased neocortex size of primates by providing a tunable pro-proliferative signal to basal progenitor cells in the subventricular zone.

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  1. Epiregulin is a member of the epidermal growth factor family. Epiregulin can function as a ligand of epidermal growth factor receptor.

    It seems i am missing the relation of epiregulin and brain evolution.

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