ARHGAP11B | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Aliases | ARHGAP11B, B'-T, FAM7B1, Rho GTPase activating protein 11B, GAP (1-8), ArhGAP11B and human encephalisation | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 616310; GeneCards: ARHGAP11B; OMA:ARHGAP11B - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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.[3]
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.[3]
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.[4] It has been reported[5] 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.[citation needed]
Human evolution
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Changes in ARHGAP11B are one of several key genetic factors of recent brain evolution and difference of modern humans to (other) apes and Neanderthals.[6] 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".[7]
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.[8] This revealed that ARHGAP11B is the gene responsible for the development of the neocortex during human evolution.
References
- ^ a b c ENSG00000286139, ENSG00000285077 GRCh38: Ensembl release 89: ENSG00000274734, ENSG00000286139, ENSG00000285077 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b Florio M, Albert M, Taverna E, Namba T, Brandl H, Lewitus E, et al. (March 2015). "Human-specific gene ARHGAP11B promotes basal progenitor amplification and neocortex expansion". Science. 347 (6229): 1465–1470. Bibcode:2015Sci...347.1465F. doi:10.1126/science.aaa1975. PMID 25721503. S2CID 34506325.
- ^ Schuster S, Rivalan M, Strauss U, Stoenica L, Trimbuch T, Rademacher N, et al. (September 2015). "NOMA-GAP/ARHGAP33 regulates synapse development and autistic-like behavior in the mouse". Molecular Psychiatry. 20 (9): 1120–1131. doi:10.1038/mp.2015.42. PMID 25869807. S2CID 21934291.
- ^ Namba T, Dóczi J, Pinson A, Xing L, Kalebic N, Wilsch-Bräuninger M, et al. (March 2020). "Human-Specific ARHGAP11B Acts in Mitochondria to Expand Neocortical Progenitors by Glutaminolysis". Neuron. 105 (5): 867–881.e9. doi:10.1016/j.neuron.2019.11.027. PMID 31883789.
- ^ "'Breakthrough' finding shows how modern humans grow more brain cells than Neanderthals". Science. Retrieved 19 October 2022.
- ^ Florio M, Namba T, Pääbo S, Hiller M, Huttner WB (December 2016). "A single splice site mutation in human-specific ARHGAP11B causes basal progenitor amplification". Science Advances. 2 (12): e1601941. Bibcode:2016SciA....2E1941F. doi:10.1126/sciadv.1601941. PMC 5142801. PMID 27957544.
- ^ 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
Further reading
- Sudmant PH, Kitzman JO, Antonacci F, Alkan C, Malig M, Tsalenko A, et al. (October 2010). "Diversity of human copy number variation and multicopy genes". Science. 330 (6004): 641–646. Bibcode:2010Sci...330..641S. doi:10.1126/science.1197005. PMC 3020103. PMID 21030649.
- Xing L, Kubik-Zahorodna A, Namba T, Pinson A, Florio M, Prochazka J, et al. (July 2021). "Expression of human-specific ARHGAP11B in mice leads to neocortex expansion and increased memory flexibility". The EMBO Journal. 40 (13): e107093. doi:10.15252/embj.2020107093. PMC 8246068. PMID 33938018.