1. Functional synergy of a human-specific and an ape-specific metabolic regulator in human neocortex development
- Author
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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
- Subjects
Science - 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.
- Published
- 2024
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