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

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. Huttner () and Takashi Namba ()
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Lei Xing: Max Planck Institute of Molecular Cell Biology and Genetics
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
Oskari Heikinheimo: University of Helsinki and Helsinki University Hospital
Svante Pääbo: Max Planck Institute for Evolutionary Anthropology
Wieland B. Huttner: Max Planck Institute of Molecular Cell Biology and Genetics
Takashi Namba: University of Helsinki

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47437-8

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