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

Nat Commun. 2024 Apr 24;15(1):3468. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Citric Acid Cycle / genetics
  • Female
  • GTPase-Activating Proteins* / genetics
  • GTPase-Activating Proteins* / metabolism
  • Glutamate Dehydrogenase* / genetics
  • Glutamate Dehydrogenase* / metabolism
  • Glutamic Acid / metabolism
  • Humans
  • Ketoglutaric Acids / metabolism
  • Mice
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Neocortex* / cytology
  • Neocortex* / embryology
  • Neocortex* / growth & development
  • Neocortex* / metabolism
  • Neuroglia / metabolism


  • Glutamate Dehydrogenase
  • GLUD2 protein, human
  • GTPase-Activating Proteins
  • Ketoglutaric Acids
  • Glutamic Acid