ARHGAP11B

''ARHGAP11B'' is a human-specific gene that amplifies basal progenitors, controls neural progenitor proliferation, and contributes to neocortex folding. It is capable of causing neocortex folding in mice. This likely reflects a role for ''ARHGAP11B'' in development and evolutionary expansion of the human neocortex, a conclusion consistent with the finding that the gene duplication that created ''ARHGAP11B'' occurred on the human lineage after the divergence from the chimpanzee lineage but before the divergence from Neanderthals.

Structure

''ARHGAP11B'' encodes 267 amino acids. A truncated copy of '' ARHGAP11A'', which is found throughout the animal kingdom and encodes a Rho GTPase-activating-protein ( RhoGAP domain), ''ARHGAP11B'' comprises most of the GAP domain (until lysine-220), followed by a novel C-terminal sequence that lacks the 756 C-terminal amino acids of ''ARHGAP11A''.

Activity

In contrast to full-length ''ARHGAP11A'' and ''ARHGAP11A 1-250'', ''ARHGAP11B'', like ''ARHGAP11A1-220'', did not exhibit RhoGAP activity in a RhoA/Rho-kinase–based cell transfection assay. This indicates that the C-terminal 47 amino-acids of ''ARHGAP11B'' (after lysine-220) constitute not only a unique sequence, resulting from a frameshifting deletion, but also are functionally distinct from their counterpart in ''ARHGAP11A''. In this assay, co-expression of ''ARHGAP11B'' along with ''ARHGAP11A'' did not inhibit the latter's RhoGAP activity.

Function

''ARHGAP11B'' is involved in neocortex folding; however, its precise function remains unknown. Several genes involved in intellectual disability encode proteins with RhoGAP domains or other proteins in the Rho signalling pathway. It has been reported that it is located in mitochondria, where it binds to the adenine nucleotide translocator. It does not affect the adenine nucleotide exchange activity of the translocator, but it does lead to delayed opening of the mitochondrial permeability transition pore, thus allowing for greater sequestration of calcium. Furthermore, the presence of ARHGAP11B in the mitochondria boosts glutaminolysis, most likely due to the ability of mitochondria to sequester calcium, thereby activating mitochondrial matrix dehydrogenases in the citric acid cycle, particularly the oxoglutarate dehydrogenase complex.

Human evolution

Changes in ARHGAP11B are one of several key genetic factors of recent brain evolution and difference of modern humans to (other) apes and Neanderthals. A 2016 study suggests, one mutation, a " single nucleotide substitution underlies the specific properties of ARHGAP11B that likely contributed to the evolutionary expansion of the human neocortex".

A 2020 study found that when ARHGAP11B was introduced into the primate common marmoset, it increased radial glial cells, upper layer neurons, and brain wrinkles ( gyral and sulcus structures), leading to the expansion of the neocortex.Michael Heide, Christiane Haffner, Ayako Murayama, Yoko Kurotaki, Haruka Shinohara, Hideyuki Okano, Erika Sasaki and Wieland B. Huttner. Human-specific ARHGAP11B increases size and folding of primate neocortex in the fetal marmoset, SCIENCE,18 Jun 2020, Vol 369, Issue 6503, pp. 546-550, DOI: 10.1126/science.abb2401 This revealed that ARHGAP11B is the gene responsible for the development of the neocortex during human evolution.

References

Further reading

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Human evolution