Summary:
A comparative neurodevelopmental study led by researchers at the Center for Regenerative Therapies Dresden (CRTD) and TUD Dresden University of Technology reveals how the human neocortex expanded without requiring a radically different set of genes. By cultivating cerebral organoids derived from human, chimpanzee, and gorilla stem cells, the team discovered nearly 600 non-coding genetic switches that operate at significantly higher activity levels in human neural stem cells. These regulatory switches drive enhanced cell branching, allowing human neural progenitors to capture environmental cues, divide more frequently, and produce the vast pool of neurons characteristic of the human brain.
Key Facts:
- Regulatory Switches Over Novel Genes: While human, chimpanzee, and gorilla coding genomes share 98% to 99% sequence identity, human neural stem cells display elevated activity across nearly 600 regulatory DNA switches that modulate gene expression levels.
- Progenitor Cell Morphology: Human-specific switch activity drives genes that promote long, branched cytoplasmic extensions in neural stem cells, enabling them to integrate niche signaling, maintain proliferative capacity, and generate more neurons.
- Organoids as Ethical Windows: By utilizing 3D brain organoids grown from induced pluripotent stem cells, the researchers bypassed the ethical and physical impossibility of sampling protected great ape embryonic brain tissue.
Source: TUD Dresden University of Technology / CRTD
The evolutionary expansion of the neocortex, the cerebral seat of abstract reasoning, long-term strategic planning, complex tool usage, and human language, represents one of evolutionary biology’s greatest structural achievements. While human brains are substantially larger than those of our closest living relatives, chimpanzees and gorillas, identifying the genomic mechanisms responsible has long confounded geneticists.
Protein-coding sequences between humans and great apes are 98% to 99% identical. Although a small handful of human-specific gene duplications have been described, these isolated factors cannot account for the massive scale of human neocortical neuron production.
Because brain enlargement is fundamentally determined during early embryogenesis when neural progenitors generate the vast majority of cortical neurons, understanding this divergence requires studying early brain development. However, developing brain tissue from non-human great apes is both strictly protected and ethically inaccessible for direct biological research.
To circumvent this barrier, an international research initiative led by Prof. Mareike Albert, research group leader at the Center for Regenerative Therapies Dresden (CRTD) and the Faculty of Biology at TUD Dresden University of Technology, turned to comparative stem cell models.
Publishing their findings, the team grew three-dimensional cerebral organoids from human, chimpanzee, and gorilla stem cells side-by-side to track the molecular programs governing early neocortical assembly.
Tuning the Genomic Dimmers
The team analyzed gene activity within radial glia and neural stem cells within the developing organoids. Rather than finding a suite of unique human-only structural genes, they identified differences in how shared genes are regulated.
“These genetic switches are short DNA sequences that control how active a gene is. You can think of them as sort of dimmers that turn genes up or down,” explains Dr. Schütze, who spearheaded the experimental work. “We found nearly 600 switches that are more active in human neural stem cells than in those of chimpanzees and gorillas.”
These regulatory elements act as transcriptional enhancers, dialing up expression of conserved cellular machinery during neurogenesis.
A substantial fraction of the genes governed by these hyperactive switches code for cytoskeletal and structural proteins that dictate cell morphology, specifically promoting the outgrowth of long, branched cytoplasmic processes.
Cell Branching and Neuron Output
To test whether this altered morphology directly dictates neurogenic capacity, the researchers experimentally silenced two of these switch-regulated genes within human cerebral organoids.
The consequences were immediate:
- Loss of Structural Complexity: Neural stem cells lost their extensive arborization and became noticeably less branched.
- Diminished Neurogenesis: In targeted knockdowns, simplified stem cells exhibited reduced proliferative division, generating significantly fewer neurons over time.
These experimental perturbations support an emerging model of cortical expansion: progenitor cells featuring elaborate morphological branches can establish more contact points within the local stem cell niche, intercepting proliferative biochemical signals from their microenvironment. This sustained signaling delays premature differentiation, allowing human neural progenitors to divide repeatedly and generate a larger pool of neocortical neurons.
“It is not necessarily different genes that make a human brain special. As the nearly identical genomes suggest, we use largely the same toolkit as apes, just with different settings,” says Prof. Albert.
Opening the Black Box of Hominid Evolution
By utilizing induced pluripotent stem cells, the team demonstrated the power of organoid platforms to address evolutionary questions that were previously considered untouchable.
“Organoids give us a window into a stage of development that we otherwise could not study at all,” Prof. Albert notes. “What makes us human is a fascinating question. With organoids, we can finally start answering parts of this question at the level of individual cells and genes.”
The findings demonstrate that evolutionary morphological leaps often stem from fine-tuning gene expression dynamics rather than introducing entirely new protein sequences. Mapping these specific regulatory dimmers provides a high-resolution foundation for understanding both primate brain evolution and neurodevelopmental conditions linked to human cortical malformations.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this neuroscience Research:
- Media Contact: Benjamin Griebe
- Source: TUD
- Image Credit: Image credited to Theresa Schütze / CRTD
- Original Research is Open Access: Nature Communications (Nov 1, 2026). “Human-specific morphoregulatory signatures in basal radial glia characterise neocortex evolution.” Authors: Theresa M. Schütze, Annika Kolodziejczyk, Nora Ditzer, Silvia Vangelisti, Emanuele Capra, Jeong-Eun Lee, Ilaria Chiaradia, Vida Kufrin, Seiya Yamada, Jula Peters, Maximilian Krause, Christina Eugster Oegema, Razvan P. Derihaci, Cahit Birdir, Takashi Namba, Alexander A. Wurm, Ulrich Martin, Pauline Wimberger, Katherine R. Long, Madeline A. Lancaster, Nereo Kalebic, Boyan Bonev & Mareike Albert.
- DOI: 10.1038/s41467-026-78474-0
Abstract
Human-specific morphoregulatory signatures in basal radial glia characterise neocortex evolution
As the seat of our cognition, the human neocortex is an object of immense fascination. Human neocortex expansion during evolution has been attributed to an increase in the proliferative capacity of neural progenitor cells during development, particularly basal radial glia.
Despite their evolutionary relevance, the genomic changes driving human basal radial glia biology remain uncharacterised.
We use comparative chromatin and transcriptional profiling of neural progenitor cells isolated from gorilla, chimpanzee and human cerebral organoids to identify cis-regulatory elements that have gained activity in humans.
Focusing specifically on basal radial glia, we discover that morphoregulatory enhancer activity and gene expression signatures distinguish human basal radial glia from other great apes.
Functional analysis of the morphoregulatory genes FAM107A and CNGA3 in human organoids reveals that these genes contribute to the morphological complexity of human basal radial glia. Taken together, our inter-species comparison of basal radial glia suggests that human-specific morphoregulatory signatures characterise neocortex evolution.
