During evolution, the size of the human brain increased significantly compared to other primates, a change that was particularly pronounced during early evolution, when the size of the brain was changing rapidly in humans.
In the lab of Wieland Huttner, a founding director of the Max Planck Institute of Molecular Cell Biology and Genetics, scientists learned that the ARHGAP11B gene, which is carried by humans, and was also present in Neanderthals and Denisovans, plays a role in regulating stem cells in the brain. In 2015, the Huttner lab investigated gene expression in various types of stem cells in the brain. They found that the ARHGAP11B gene increased the number of basal progenitor cells that give rise to neurons; this increased number of basal brain stem cells leads to a larger brain with more folds. They suggested that this gene was likely to have played a significant role in the evolution of the complex human brain.
Scientists in the Huttner lab have now learned more about the function of the ARHGAP11B gene. It encodes for a protein that can be found in the cell’s powerhouse, an organelle called the mitochondrion. The protein can trigger a metabolic pathway in stem cells. The pathway, called glutaminolysis, is also known to provide energy to growing cancer cells. The findings, which revealed a mechanism underlying the proliferation of brain cells in humans, have been reported in Neuron.
"We found that ARHGAP11B interacts with a protein in the membrane of mitochondria that regulates a membrane pore. As a consequence of this interaction, the pores in the membrane are closing up, preventing calcium leakage from the mitochondria. The resulting higher calcium concentration causes the mitochondria to generate chemical energy by a metabolic pathway called glutaminolysis. In this way, ARHGAP11B can trigger basal brain stem cells to form a larger pool of stem cells," explained postdoctoral researcher Takashi Namba, the first author of the study.
"An increase in glutaminolysis is a hallmark of highly proliferating cells, notably tumor cells. Thus, ARHGAP11B may have contributed to the evolutionary expansion of the human brain by inducing a cancer-like metabolism in the basal brain stem cells for a limited period during brain development," added Huttner, the senior author of the study.