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Functional synergy of a human-specific and an ape-specific metabolic regulator in human neocortex development

Author

Listed:
  • Lei Xing

    (Max Planck Institute of Molecular Cell Biology and Genetics
    University of Manitoba)

  • Vasiliki Gkini

    (University of Helsinki)

  • Anni I. Nieminen

    (University of Helsinki)

  • Hui-Chao Zhou

    (VIB-KU Leuven)

  • Matilde Aquilino

    (University of Helsinki)

  • Ronald Naumann

    (Max Planck Institute of Molecular Cell Biology and Genetics)

  • Katrin Reppe

    (Max Planck Institute of Molecular Cell Biology and Genetics)

  • Kohichi Tanaka

    (Tokyo Medical and Dental University)

  • Peter Carmeliet

    (Department of Oncology, KU Leuven
    Center for Cancer Biology, VIB
    Khalifa University of Science and Technology)

  • Oskari Heikinheimo

    (University of Helsinki and Helsinki University Hospital)

  • Svante Pääbo

    (Max Planck Institute for Evolutionary Anthropology
    Okinawa Institute of Science and Technology)

  • Wieland B. Huttner

    (Max Planck Institute of Molecular Cell Biology and Genetics)

  • Takashi Namba

    (University of Helsinki)

Abstract

Metabolism has recently emerged as a major target of genes implicated in the evolutionary expansion of human neocortex. One such gene is the human-specific gene ARHGAP11B. During human neocortex development, ARHGAP11B increases the abundance of basal radial glia, key progenitors for neocortex expansion, by stimulating glutaminolysis (glutamine-to-glutamate-to-alpha-ketoglutarate) in mitochondria. Here we show that the ape-specific protein GLUD2 (glutamate dehydrogenase 2), which also operates in mitochondria and converts glutamate-to-αKG, enhances ARHGAP11B’s ability to increase basal radial glia abundance. ARHGAP11B + GLUD2 double-transgenic bRG show increased production of aspartate, a metabolite essential for cell proliferation, from glutamate via alpha-ketoglutarate and the TCA cycle. Hence, during human evolution, a human-specific gene exploited the existence of another gene that emerged during ape evolution, to increase, via concerted changes in metabolism, progenitor abundance and neocortex size.

Suggested Citation

  • Lei Xing & Vasiliki Gkini & Anni I. Nieminen & Hui-Chao Zhou & Matilde Aquilino & Ronald Naumann & Katrin Reppe & Kohichi Tanaka & Peter Carmeliet & Oskari Heikinheimo & Svante Pääbo & Wieland B. Hutt, 2024. "Functional synergy of a human-specific and an ape-specific metabolic regulator in human neocortex development," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47437-8
    DOI: 10.1038/s41467-024-47437-8
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    References listed on IDEAS

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    1. Tae-Yeon Eom & Amelia Stanco & Jill Weimer & Kristen Stabingas & Elizabeth Sibrack & Vladimir Gukassyan & JrGang Cheng & E.S. Anton, 2011. "Direct visualization of microtubules using a genetic tool to analyse radial progenitor-astrocyte continuum in brain," Nature Communications, Nature, vol. 2(1), pages 1-6, September.
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