Studies in mouse and ferret neocortex – the brain region responsible for higher-order functions – previously demonstrated a role for the human-specific gene, ARHGAP11B, in neocortical expansion (see BioNews 792). ARHGAP11B arose around five million years ago through partial duplication of a similar gene, ARHGAP11A. Later, a mutation in ARHGAP11B resulted in a sequence that is unique to humans and is essential for brain stem cells to multiply. Now, researchers in Germany and Japan have investigated this gene in non-human primates to more accurately model human brain development.
'In light of potential unforeseeable consequences with regard to postnatal brain function, we considered it a prerequisite – and mandatory from an ethical point of view – to first determine the effects of ARHGAP11B on the development of fetal marmoset neocortex.' said Professor Wieland Huttner, the research group leader at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany.
With Japanese collaborators at the Central Institute for Experimental Animals in Kawasaki and the Keio University in Tokyo, the scientists induced expression of ARHGAP11B in neonatal marmosets. The team constructed a lentiviral vector to express both ARHGAP11B and an enhanced green fluorescent protein (EGFP) reporter, such that cells which express ARHGAP11B fluoresce green. The vector was injected into fertilised marmoset oocytes in vitro, and the developed marmoset embryos with the spliced human-specific gene were transferred into marmosets for the transgenic fetus to grow.
Transferring human genes into another species to form, in this case, a human-monkey hybrid (a transgenic non-human primate) poses many ethical concerns. Hence, the researchers did not allow the pregnancies to develop to full term, and the fetuses were collected via caesarean section at day 101 of the 150-day gestation period.
Of the seven transgenic marmoset fetuses collected, five expressed both EGFP and ARHGAP11B in the neocortex. ARHGAP11B-expressing marmoset neocortex was larger and exhibited surface folds, whereas normal marmoset brain is smooth. These folds allow for a greater surface area of brain and are a characteristic of higher intelligence.
Dr Michael Heide, lead author of the study, said 'We found indeed that the neocortex of the common marmoset brain was enlarged and the brain surface folded'.
The neocortex is, evolutionarily, the youngest part of the brain and is responsible for intelligent processes, such as reasoning and language. This study has demonstrated that ARHGAP11B causes an expansion of the primate neocortex, which may explain why the human neocortex is three-fold larger than that of chimpanzees, our closest relative.
'Such point mutations occur relatively frequently, but in the case of ARHGAP11B its advantages of forming a bigger brain seem to have immediately influenced human evolution' added Professor Huttner.
This research was recently published in the journal Science.