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

• Published in: Nature communications 2024-04, Vol.15 (1), p.3468-3468, Article 3468
• Main Authors: Xing, Lei, Gkini, Vasiliki, Nieminen, Anni I., Zhou, Hui-Chao, Aquilino, Matilde, Naumann, Ronald, Reppe, Katrin, Tanaka, Kohichi, Carmeliet, Peter, Heikinheimo, Oskari, Pääbo, Svante, Huttner, Wieland B., Namba, Takashi
• Format: Article
• Language: English
• Subjects: 13/100; 14/19; 631/181/2806; 631/378/2571; 631/45/320; 64/60; Animals; Cell proliferation; Cell size; Cerebral cortex; Citric Acid Cycle - genetics; Enzymes; Evolution; Female; Glial stem cells; Glutamate dehydrogenase; Glutamate Dehydrogenase - genetics; Glutamate Dehydrogenase - metabolism; Glutamic Acid - metabolism; Glutamine; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Humanities and Social Sciences; Humans; Ketoglutaric acid; Ketoglutaric Acids - metabolism; Metabolism; Metabolites; Mice; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; multidisciplinary; Neocortex; Neocortex - cytology; Neocortex - embryology; Neocortex - growth & development; Neocortex - metabolism; Neuroglia - metabolism; Radial glial cells; Science; Science (multidisciplinary); Tricarboxylic acid cycle
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-47437-8

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. Cell metabolism has emerged as a major factor implicated in human brain evolution. Here, the authors show that an ape-specific enzyme enhances the ability of a human-specific enzyme to increase glutaminolysis and therefore expand the size of the human neocortex.