Evolutionary Expansion of the Human Forebrain
Post by Amanda McFarlan
What's the science?
The human brain rapidly expanded in size following our divergence from other great apes. Relative to other mammals, the human brain is enlarged and has a higher number of neurons. However, the mechanisms underlying this human brain expansion relative to other mammals remain unclear. This week in Cell, Benito-Kwiecinski and colleagues used cerebral organoids (tissue grown in a lab that mimics brain cells) to investigate the early developmental processes prior to neurogenesis in human, gorilla, and chimpanzee brains. They primarily focused on studying the transitional period during which precursor cells, known as neuroepithelial cells, become radial glia cells, triggering the onset of neurogenesis (the formation of new neurons).
How did they do it?
Using human, gorilla, and chimpanzee cell lines, the authors generated cerebral organoids to study differences in brain development across these three species. They used several methods including reverse transcription PCR, immunofluorescent staining, and live imaging to examine neuroepithelial expansion, nuclear migration, and cell cycles in the cerebral organoids at several time points during development. Then, to identify the biological factors that might be involved in mediating the shift from neuroepithelial cell to radial glial during brain development, the authors used RNA-sequencing and time course sequencing to examine changes in gene expression in human and gorilla organoids at multiple time points between day 0 (pre-neurulation) and day 25 (neurogenesis). This revealed a difference in expression of the gene ZEB2 (a transcription factor), which the authors confirmed by western blot and imaging in both human and gorilla organoids. Finally, the authors developed ZEB2 mutant human embryonic stem cells that were heterozygous for the ZEB2 gene to investigate the role of ZEB2 in the transition from neuroepithelial cell to radial glia. Furthermore, they examined how altering the timing of ZEB2 expression during development affects this transition period in human and gorilla organoids.
What did they find?
The authors found that human organoids showed greater neuroepithelial expansion prior to neurogenesis compared to gorilla and chimpanzee organoids. All organoids underwent a transition state prior to the change from neuroepithelial cell to radial glia, however, this transition state was shorter and delayed in the human organoids relative to the gorilla organoids. Then, the authors revealed that while genes associated with neurogenesis and RNA processing had identical clustering among the species, genes associated with cell morphogenesis and the epithelial-to-mesenchymal transition (a process by which cells gradually lose epithelial features and become neurons) clustered differently between species. They identified the transcription factor ZEB2 as a likely candidate for regulating the transitional period from epithelial cell to radial glia since ZEB2 is known to be involved in the epithelial-to-mesenchymal transition. The authors showed that ZEB2 expression increased in gorilla and human neuroepithelial cells that were transitioning into radial glia cells and that heterozygous expression of ZEB2 in human neuroepithelial cells disrupted this transition. They also found that earlier expression of ZEB2 in human organoids resulted in neuroepithelial cells that more closely resembled those observed in gorilla organoids. Similarly, delayed expression of ZEB2 in gorilla organoids resulted in neuroepithelial cells that more closely resembled those observed in human organoids.
What’s the impact?
This study is the first to show evidence of differences between species in a transitional stage that occurs during the switch from neuroepithelial cell to radial glia. Using cerebral organoids, the authors demonstrated that this transitional stage is delayed in humans and mediated by the expression of ZEB2, resulting in more expanded brains in humans. Together, these findings highlight how differences in the timing of early developmental processes can have a major impact on overall brain evolution across mammalian species.
Benito-Kwiecinski et al. An early cell shape transition drives evolutionary expansion of the human forebrain. Cell (2021). Access the original scientific publication here.