ARHGAP11B

ARHGAP11B
Identifiers
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
Gene location (Human)
Chr.	Chromosome 15 (human)
End	30,649,529 bp
RNA expression pattern
	Top expressed in
	testicle; ; bone marrow; ; bone marrow cells; ; ganglionic eminence; ; stromal cell of endometrium; ; ventricular zone; ; gonad; ; lymph node; ; monocyte; ; appendix;
	n/a
	More reference expression data
	n/a
Gene ontology
Molecular function	GTPase activator activity;
Cellular component	cytosol;
Biological process	regulation of small GTPase mediated signal transduction; signal transduction; cerebral cortex development; positive regulation of GTPase activity;
	Sources:Amigo / QuickGO
Orthologs
	89839
	n/a
	ENSG00000274734; ENSG00000286139; ENSG00000285077
	n/a
	Q3KRB8
	n/a
	NM_001039841
	n/a
	NP_001034930
	n/a
	Wikidata
View/Edit Human

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

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