RESUMO
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.
Assuntos
Proteínas Ativadoras de GTPase , Glutamato Desidrogenase , Neocórtex , Neocórtex/metabolismo , Neocórtex/embriologia , Neocórtex/crescimento & desenvolvimento , Neocórtex/citologia , Humanos , Animais , Glutamato Desidrogenase/metabolismo , Glutamato Desidrogenase/genética , Proteínas Ativadoras de GTPase/metabolismo , Proteínas Ativadoras de GTPase/genética , Ácidos Cetoglutáricos/metabolismo , Neuroglia/metabolismo , Ácido Glutâmico/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/genética , Camundongos , Ciclo do Ácido Cítrico/genética , FemininoRESUMO
Multiple types of neural progenitor cells (NPCs) contribute to the development of the neocortex, a brain region responsible for our higher cognitive abilities. Proliferative capacity of NPCs varies among NPC types, developmental stages, and species. The higher proliferative capacity of NPCs in the developing human neocortex is thought to be a major contributing factor why humans have the most expanded neocortex within primates. Recent studies have shed light on the importance of cell metabolism in the neocortical NPC proliferative capacity. Specifically, glutaminolysis, a metabolic pathway that converts glutamine to glutamate and then to α-ketoglutarate, has been shown to play a critical role in human NPCs, both in apical and basal progenitors. In this review, we summarize our current knowledge of NPC metabolism, focusing especially on glutaminolysis, and discuss the role of NPC metabolism in neocortical development, evolution, and neurodevelopmental disorders, providing a broader perspective on a newly emerging research field.
