Alternative titles; symbols
HGNC Approved Gene Symbol: ARHGAP11B
Cytogenetic location: 15q13.2 Genomic coordinates (GRCh38) : 15:30,626,128-30,649,229 (from NCBI)
Cortical expansion in humans has been linked to increased generation of basal progenitor cells from apical radial glia and their greater and prolonged proliferation, resulting in enlargement of the subventricular zone. By analyzing the transcriptomes of progenitor cell subpopulations from developing mouse and human neocortex, Florio et al. (2015) identified 56 human-specific genes that were preferentially expressed in apical and basal radial glia. Among these, ARHGAP11B showed the highest degree of radial glia-specific expression. The deduced 267-amino acid ARHGAP11B protein is a truncated version of ARHGAP11A (610589) that includes most of the GTPase-activating protein (GAP) domain (up to lys220), but it has a unique C-terminal 47 amino acids due to a frameshift. ARHGAP11B mRNA was highly expressed in both apical and basal radial glia, but it was virtually undetectable in cortical neurons and cortical plate, as confirmed by single-cell quantitative PCR.
By immunofluorescence analysis, Namba et al. (2020) showed that human ARHGAP11B localized to mitochondria in transfected NIH3T3 cells and that the N-terminal mitochondrial targeting sequence of ARHGAP11B was required and sufficient for the localization. ARHGAP11B also localized to mitochondria in progenitors of fetal human neocortex.
In contrast with full-length ARHGAP11A and its isolated GAP domain, Florio et al. (2015) found that ARHGAP11B exhibited no RhoGAP activity in a RhoA (165390)/Rho-kinase (ROCK1; 601702)-based assay. ARHGAP11A truncated at lys220 also showed no RhoGAP activity. In utero electroporation of ARHGAP11B in mouse neocortex at embryonic day 13.5 (E13.5) increased basal, but not apical, progenitor mitosis, resulting in thickening of the subventricular zone and neocortical folding at E18.5, reminiscent of gyrification.
Heide et al. (2020) found that transgenic expression of human ARHGAP11B under control of its own (human) promoter in fetal marmosets increased the numbers of basal radial glia progenitors in the marmoset outer subventricular zone, increased the numbers of upper-layer neurons, enlarged the neocortex, and induced neocortical folding. The results suggested that ARHGAP11B expression might be one of the causes of the more robust neocortex that characterizes human brain.
Using embryonic mouse neocortex as a test system, Namba et al. (2020) demonstrated that human ARHGAP11B increased the abundance and proliferation of basal progenitors (BPs). The ability to expand BPs by ARHGAP11B required its mitochondrial localization but was blocked by expression of excess Ant2 (SLC25A5; 300150). ARHGAP11B bound directly to Ant2 via its GAP domain, inhibited Ant2 to delay the opening of the mitochondrial permeability transition pore, and thereby increased BP abundance. The C-terminal domain of ARHGAP11B was responsible for the inhibitory effect on Ant2 function and for the increase in BP abundance. In addition, glutaminolysis was essential for ARHGAP11B-induced BP expansion, as glutamine-to-glutamate conversion was required in the process. Delayed opening of the mitochondrial permeability transition pore induced by ARHGAP11B increased mitochondrial Ca(2+) levels, which in turn promoted glutaminolysis required for proliferation of BPs.
Florio et al. (2015) determined that the ARHGAP11B gene contains 7 exons and spans 12.13 kb.
Florio et al. (2015) reported that the ARHGAP11B gene maps to chromosome 15q13.2.
Florio et al. (2015) determined that ARHGAP11B arose from partial duplication of the ARHGAP11A gene in the human lineage after divergence from chimpanzees, but before divergence from Neandertals.
Florio, M., Albert, M., Taverna, E., Namba, T., Brandl, H., Lewitus, E., Haffner, C., Sykes, A., Wong, F. K., Peters, J., Guhr, E., Klemroth, S., Prufer, K., Kelso, J., Naumann, R., Nusslein, I., Dahl, A., Lachmann, R., Paabo, S., Huttner, W. B. Human-specific gene ARHGAP11B promotes basal progenitor amplification and neocortex expansion. Science 347: 1465-1470, 2015. [PubMed: 25721503] [Full Text: https://doi.org/10.1126/science.aaa1975]
Heide, M., Haffner, C., Murayama, A., Kurotaki, Y., Shinohara, H.,, Okano, H., Sasaki, E., Huttner, W. B. Human-specific ARHGAP11B increases size and folding of primate neocortex in the fetal marmoset. Science 369: 546-550, 2020. [PubMed: 32554627] [Full Text: https://doi.org/10.1126/science.abb2401]
Namba, T., Doczi, J., Pinson, A., Xing, L., Kalebic, N., Wilsch-Brauninger, M., Long, K. R., Vaid, S., Lauer, J., Bogdanova, A., Borgonovo, B., Shevchenko, A., Keller, P., Drechsel, D., Kurzchalia, T., Wimberger, P., Chinopoulos, C., Huttner, W. B. Human-specific ARHGAP11B acts in mitochondria to expand neocortical progenitors by glutaminolysis. Neuron 105: 867-881, 2020. [PubMed: 31883789] [Full Text: https://doi.org/10.1016/j.neuron.2019.11.027]