2021/01/06
Keio University School of Medicine
A research group including Associate Professor Masaaki Torii and Associate Professor Kazue Hashimoto-Torii of Children's National Hospital in the United States, Professor Pasko Rakic of Yale University in the United States, Project Lecturer Seiji Ishii and Professor Hideyuki Okano of the Department of Physiology, Keio University School of Medicine, has used primary cilia-deficient mice to elucidate the protective role of primary cilia—which appear as small "hairs" on the cell surface—in shielding the neonatal cerebral cortex from environmental stress, and has uncovered the detailed mechanism behind it.
We are exposed to various hazards in our lives, such as environmental pollutants like chemical substances that raise concerns about their impact on human health, as well as viruses and bacteria that cause infectious diseases. These unfavorable external factors for living organisms are referred to as "environmental stress." During the "critical period" in early postnatal life, a time when neural networks change flexibly in response to experience, there is a window when the cerebral cortex's resistance to various environmental stresses is reduced. Therefore, the research team focused on primary cilia, which particularly elongate during this period.
First, the research team created mice with a primary cilia deficiency only in the cerebral cortex. When these mice were exposed to environmental stress during the critical period, the team found a large number of punctate activated caspase-3 signals, particularly in the neurons of layer V of the cerebral cortex. The team then conducted a detailed examination of the layer V neurons in the cerebral cortex of primary cilia-deficient mice exposed to environmental stress. They revealed that while the number of neurons did not decrease, the length and number of branches of their dendrites were reduced, showing signs of degeneration. Next, the team searched for an environmental stress-responsive intracellular signaling pathway that is activated in a primary cilia-dependent manner. They discovered that activated insulin-like growth factor 1 receptors accumulate on the primary ciliary membrane of cerebral cortical neurons, activating the PI3K/Akt signaling pathway. Furthermore, they found that administering a drug that activates the Akt protein to primary cilia-deficient mice simultaneously with alcohol could rescue the dendritic degeneration in the cerebral cortex. These findings suggest that after the critical period, neurons in the cerebral cortex acquire a resistance mechanism to environmental stress that originates from primary cilia.
The results of this research were published in the January 5, 2021, issue of the scientific journal "Proceedings of the National Academy of Sciences of the United States of America" (EST).
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