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Neuron. 2019 Dec 13. pii: S0896-6273(19)31036-0. doi: 10.1016/j.neuron.2019.11.027. [Epub ahead of print]

Human-Specific ARHGAP11B Acts in Mitochondria to Expand Neocortical Progenitors by Glutaminolysis.

Author information

1
Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstraße 108, 01307 Dresden, Germany. Electronic address: namba@mpi-cbg.de.
2
Department of Medical Biochemistry, Semmelweis University, Budapest, Tuzolto St. 37-47 1094, Hungary.
3
Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstraße 108, 01307 Dresden, Germany.
4
Universitätsklinikum Carl Gustav Carus, Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Technische Universität Dresden, Dresden, Germany.
5
Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstraße 108, 01307 Dresden, Germany. Electronic address: huttner@mpi-cbg.de.

Abstract

The human-specific gene ARHGAP11B is preferentially expressed in neural progenitors of fetal human neocortex and increases abundance and proliferation of basal progenitors (BPs), which have a key role in neocortex expansion. ARHGAP11B has therefore been implicated in the evolutionary expansion of the human neocortex, but its mode of action has been unknown. Here, we show that ARHGAP11B is imported into mitochondria, where it interacts with the adenine nucleotide translocase (ANT) and inhibits the mitochondrial permeability transition pore (mPTP). BP expansion by ARHGAP11B requires its presence in mitochondria, and pharmacological inhibition of ANT function or mPTP opening mimic BP expansion by ARHGAP11B. Searching for the underlying metabolic basis, we find that BP expansion by ARHGAP11B requires glutaminolysis, the conversion of glutamine to glutamate for the tricarboxylic acid (TCA) cycle. Hence, an ARHGAP11B-induced, mitochondria-based effect on BP metabolism that is a hallmark of highly mitotically active cells appears to underlie its role in neocortex expansion.

KEYWORDS:

evolution; metabolism; neocortex; neural progenitor cells

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