TY - JOUR
T1 - Functional synergy of a human-specific and an ape-specific metabolic regulator in human neocortex development
AU - Xing, Lei
AU - Gkini, Vasiliki
AU - Nieminen, Anni I.
AU - Zhou, Hui-Chao
AU - Aquilino, Matilde
AU - Naumann, Ronald
AU - Reppe, Katrin
AU - Tanaka, Kohichi
AU - Carmeliet, Peter
AU - Heikinheimo, Oskari
AU - Pääbo, Svante
AU - Huttner, Wieland B.
AU - Namba, Takashi
PY - 2024/4
Y1 - 2024/4
N2 - 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.
AB - 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.
KW - 1182 Biochemistry, cell and molecular biology
KW - 116 Chemical sciences
KW - 3112 Neurosciences
U2 - 10.1038/s41467-024-47437-8
DO - 10.1038/s41467-024-47437-8
M3 - Article
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
M1 - 3468
ER -