Science Breakthrough: Human specific gene ARHGAP11B makes monkey brains more like humans?

Recently, Researchers at Max Planck Institute of Molecular Cell Biology and Genetics published a paper “Human-specific ARHGAP11B increasessize and folding of primate neocortex in the fetal marmoset” in Science. This study provides functional evidence that ARHGAP11B causes expansion of the primate neocortex. 

The expansion of human brain during the evolution, especially of the neocortex, is associated with cognitive abilities such as reasoning and language. A specific gene named ARHGAP11B, which only expresses in humans, can trigger brain stem cells to form more stem cells, a prerequisite for a bigger brain. Overexpression studies in developing mouse and ferret neocortex have implicated the human-specific gene ARHGAP11B in neocortical expansion, but the relevance for primate evolution has been unclear.

Microscopy image of a section through one brain hemisphere of a 101 day- old ARHGAP11B-transgenic marmoset fetus.

Cell nuclei are visualized by DAPI (white). Arrows indicate a sulcus and a gyrus. Credit: Heide et al. / MPI-CBG

In order to research this problem, the researchers in the group of Wieland Huttner, Cooperated with colleagues at the Central Institute for Experimental Animals (CIEA) in Kawasaki and at the Keio University in Tokyo, who had pioneered a technology to generate transgenic non-human primates. They generated transgenic common marmosets that expressed the human-specific gene ARHGAP11B, which they normally do not have, in the developing neocortex. Japan has similarly high ethical standards and regulations regarding animal research and animal welfare as Germany does. The brains of 101-day-old common marmoset fetuses (50 days before the normal birth date) were obtained in Japan and exported to the MPI-CBG in Dresden for detailed analysis. 

Researchers found that ARHGAP11B expressed in fetal neocortex of the common marmoset under control of the gene’s own, human, promoter increased numbers of basal radial glia progenitors in the marmoset outer subventricular zone, increased numbers of upper-layer neurons, enlarged the neocortex, and induced its folding. The researchers had now functional evidence that ARHGAP11B causes an expansion of the primate neocortex.

Wildtype (normal) and ARHGAP11B-transgenic fetal (101 days) marmoset brains.
Yellow lines, boundaries of cerebral cortex; white lines, developing cerebellum; arrowheads, folds.
Scale bars, 1 mm. Credit: Heide et al. / MPI-CBG
Moral considerations

Wieland Huttner, who led the study, adds: "We confined our analyses to marmoset fetuses, because we anticipated that the expression of this human-specific gene would affect the neocortex development in the marmoset. 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."

This study suggest that the human-specific ARHGAP11B gene may have caused neocortex expansion in the course of human evolution. Thus, the human-specific ARHGAP11B drives changes in development in the non-human primate marmoset that reflect the changes in evolution that characterize human neocortical development. So could the human-specific ARHGAP11B make monkey brains more like humans? That’s a question.

References

1. Humanbrain size gene triggers bigger brain in monkeys.

2. Heide, M., Haffner, C., Murayama, A., Kurotaki, Y., Shinohara, H., Okano, H., ... & Huttner, W. B. (2020).  "Human-specific ARHGAP11B increases size and folding of primate neocortex in the fetal marmoset." Science.


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