How did human brains get so large?
Newly found gene sheds light on human brain evolution
November 4, 2022
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Leuven, 4 November - The team of Prof. Pierre Vanderhaeghen at the VIB-KU Leuven Center for Brain & Disease Research and Université Libre de Bruxelles (ULB) discovered a gene that may have been essential for the expansion of human brain size during evolution. The CROCCP2 gene, previously thought to be inactive, is actually highly expressed in the human fetal brain and could be responsible for the diversity of cells in the brain. This discovery may have important implications for human evolution and disease.
Key points
- Previously thought to be inactive, the CROCCP2 gene is essential for the diversity of cells in the human brain.
- Humans are the only species in which CROCCP2 is active in the brain, suggesting that the gene plays a vital role in human brain evolution.
- CROCCP2 increases an important pathway called mTOR, which is also affected in several brain diseases.
- The study shows how our brains developed a sensitivity to certain diseases by becoming larger and more complex.
Brain evolution
The human brain has come a long way. Throughout human evolution, it has become an incredibly complex organ with specialized regions that have distinctive features and functions. The many different types of brain cells are the foundation of the brain's complexity, which has given our success as species a big boost. How the human brain differentiated from other great apes is still largely unknown, but researchers believe 'hominid-specific' genes have been essential in human brain formation. These genes emerged through genetic duplications, a copy-paste mechanism that caused the rapid occurrence of new genes in our recent evolution. The hominid-specific gene CROCCP2 resulted from a gene duplication and is inactive. Or so we thought.
The team of Prof. Pierre Vanderhaeghen studies the mechanisms behind the evolution of the human brain and what makes it so unique and sensitive to diseases such as autism spectrum disorder, epilepsy, and schizophrenia.
Gene discovery
Even though the human genome was already fully sequenced in 2003, researchers are still analyzing the functional information hidden in our DNA. Now, Vanderhaeghen and his team discovered that the CROCCP2 gene is highly active in the human fetal brain. PhD student Roxane Van Heurck and Dr. Jerome Bonnefont work in the Vanderhaeghen lab and are the study's first authors. Their work, published in the prestigious journal Neuron, shows that CROCCP2 is necessary and sufficient for the amount and diversity of stem cells and nerve cells in the human brain. This expansion is thought to be critical for the region of the brain responsible for the higher cognition that characterizes our species. The researchers also found that the gene is highly expressed in the human fetal brain but not in other primates. This suggests that the gene played an important role in increasing human brain size and complexity in evolution.
The scientists used an array of innovative technologies in their research. Roxane: "We discovered the crucial function of CROCCP2 by studying the developing mouse brain and human brain organoids that mimic the early steps of brain development." Jerome adds: "Thanks to the organoid technology, we were able to assess the impact of CROCCP2 in human cells directly. This revealed a result that we would not have been able to predict or observe otherwise."
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Link with disease
The team further showed that the CROCCP2 gene acts by enhancing a major pathway - the mTOR-pathway - critical for cell growth and affected in human disorders such as autism spectrum disorders and brain tumors. This illustrates how our brain has developed a sensitivity to some diseases by becoming larger and more complex.
Pierre: "This discovery explains some of the mysteries surrounding brain development and evolution, with interesting links to human brain diseases. We linked CROCCP2 to the mTOR pathway, which is uniquely increased in the human brain stem cells, and tightly linked to autism spectrum disorders and specific brain tumors that mostly strike our species. Our work contributes to a better understanding of what makes the human brain so distinct from other species, which is crucial to understand these diseases."
Publication
CROCCP2 acts as a human-specific modifier of cilia dynamics and mTOR signaling to promote expansion of cortical progenitors. Van Heurck et al. Neuron, 2022.
Funding
This work was funded by Grants of the European Research Council (GENDEVOCORTEX), the Belgian FWO and FRS/FNRS, the AXA Research Fund, the Generet Fund, the Belgian Queen Elizabeth Foundation, the Fondation ULB. Roxane Van Heurck was an Aspirant of the Belgian FRS/FNRS and awardee of the L'Oréal Foundation (file number 51989).
About VIB-KU Leuven Center for Brain & Disease Research
Scientists at the VIB-KU Leuven Center for Brain & Disease study how brain cells are organized and how they communicate with each other. These mechanisms reveal and provide insights into what goes wrong in brain diseases such as Alzheimer's, Parkinson's, ALS and dystonia. This basic work should ultimately lead to new drugs for use against these currently incurable diseases.
About KU Leuven
KU Leuven is Europe’s most innovative university (Reuters) and ranks 45th in the Times Higher Education World University Rankings. As Belgium's largest university, KU Leuven welcomes 60,000 students from over 140 countries. Its 7,000 researchers are active in a comprehensive range of disciplines. KU Leuven is a founding member of the League of European Research Universities (LERU) and has a strong European and international orientation. University Hospitals Leuven, its network of research hospitals, provides high-quality healthcare and develops new therapeutic and diagnostic insights with an emphasis on translational research. More info: www.kuleuven.be/english.