Nature: Tsinghua Songhai/Shipping reveals a new mechanism for the central body to regulate the development of the cerebral cortex.

The brain is the most advanced center of the nervous system, which controls such high-level neural activities as perception, movement, language, thinking and cognition.it is very important to study the development and regulation mechanism of brain nervous system, to strengthen the cognition of nervous system, and to diagnose and treat nervous system related diseases.radial glial cells are the key neural precursor cells in mammalian brain development. They divide and produce almost all neurons and glial cells in the cerebral cortex.during brain development, the behavior of radial glial cells is highly ordered.as the main microtubule tissue center of animal cells, centrosome regulates the process of cell cycle and plays an important role in the development of brain nervous system.usually, centrosomes are located in the cytoplasm near the nucleus. However, in radial glial cells, centrosomes are located on the apical cell membrane far away from the nucleus, that is, on the surface of the ventricular cavity.this unique subcellular feature has been found for decades, but its cause and function have been puzzling.on March 25, Professor Shi Songhai of Beijing biological structure frontier research center and research group of Shi Hang researcher of advanced innovation center of structural biology published online "centrosome anchoring regulations progenitor properties and cortical" in nature This is the first time that centrosome regulates the mechanical properties and division ability of neural precursor cells in mammalian cerebral cortex, thus affecting the size and folding of cerebral cortex.in this paper, the researchers firstly observed the brain tissue of embryonic mice by using the continuous ultrathin section technology based on transmission electron microscope imaging, and observed for the first time that the centrosome in radial glial cells was anchored to the apical cell membrane through the distal appendages attached to the maternal centriole (Fig. 1).in order to explore the molecular regulatory mechanism and physiological function of centrosome localization, the researchers specifically removed cep83, an important component of the distal appendage in radial glial cells of cerebral cortex, so that no distal attachment was formed on the maternal centriole, resulting in slight dislocation of centrosome and apical membrane, thus preventing the anchoring and connection between centrosome and cell membrane（ Figure 1).Fig. 1. The centrosome was anchored to the apical membrane through the distal appendage. Interestingly, after the centrosome anchoring in radial glial cells was specifically destroyed, the cerebral cortex volume in adult mice was significantly increased, and abnormal folding was common in the dorsal raphe area of the cortex (Fig. 2 a).further studies have found that this abnormal phenotype results from the excessive proliferation of radial glial cells in the early stage of neurogenesis and the increase of intermediate precursor cells after neurogenesis (Fig. 2b).Fig. 2. How does cep83 specific knockout result in increased cortical volume and abnormal folding of nerves? Further study found that the dislocation of centrosome less than 1 μ m destroyed the unique circular microtubule structure on the apical membrane, resulting in the stretching and hardening of the apical membrane.changes in the physical properties of the apical membrane caused the Yap protein (yes associated) associated with the mechanical sensitive signal pathway in radial glial cells The excessive activation of protein leads to the excessive expansion of pre radial glial cells and the increase of intermediate precursor cells. Finally, the number of neurons in cerebral cortex increases significantly, and the volume of cortex expands, which leads to abnormal folding.consistent with this, the simultaneous knockout of Yap can restore the cortical volume to the normal level without folding (Fig. 3).Fig. 3. Centrosome anchoring regulates the mechanical properties of the apical membrane of radial glial cells and Yap signal, resulting in the increase in the number of nerve cells and the expansion of cortical volume. This study solved the long-standing mystery of the cause and role of centrosome in radial glial cells, and provided a new perspective for the study of neural precursor cell behavior and cortical development regulation.in addition, previous studies have shown that centrosome protein related mutations are generally closely related to microcephaly. However, this study found that centrosome protein mutations lead to macrocephaly, and for the first time revealed its mechanism.more importantly, human cep83 biallelic mutation can lead to ventricular volume enlargement, mental retardation and renal wasting disease in children. This study provides important clues for revealing the morphological and intellectual abnormalities of human cortex.Wei Shao of Cornell University School of medicine and Yang Jiajun, a doctoral student from the school of life sciences, Tsinghua University, are the co first authors of this paper.he Ming, PhD student of Peking University School of life, Xiangyu Sheng, School of life, Tsinghua University, Zhao Hui Yang, medical school of Cornell University, Alexandra L. Joyner, Kathryn v. Anderson, Meng Fu Bryan Tsou, Choong Heon Lee and Jiang Yang Zhang from the school of life of New York University participated in the study.Professor Shi Songhai and researcher Shi Hang of advanced innovation center of structural biology are co authors of this paper.this study is supported by Tsinghua University Life Alliance Center, Beijing advanced innovation center of structural biology and Beijing biological structure frontier research center, Beijing outstanding young scientist, NIH and Howard Hughes Institute of medicine.link: This paper is from the advanced innovation center of structural biology, Tsinghua University