May 19, 2021
Kyushu University
Nagoya University, Tokai National Higher Education and Research System
Keio University
A research group led by Assistant Professor Hideyuki Nakashima and Professor Kinichi Nakashima of the Graduate School of Medical Sciences, Kyushu University, in a joint research project with Professor Takuya Imamura of the Graduate School of Integrated Sciences for Life, Hiroshima University; Project Lecturer Keita Tsujimura of the Graduate School of Science and Institute for Advanced Research, Nagoya University; and Professor Hideyuki Okano of the Department of Physiology, Keio University School of Medicine, has discovered and clarified the mechanism by which methyl-CpG binding protein 2 (MeCP2), the causal factor for the neurodevelopmental disorder Rett syndrome, regulates the differentiation of neural stem cells via microRNA (miRNA).
Rett syndrome is a progressive neurodevelopmental disorder characterized by autism, epilepsy, ataxic gait, and a characteristic stereotyped movement (hand-wringing). Although it is known to be caused by mutations in the MeCP2 gene, the details of its pathogenesis have been unclear. This research group has revealed that during brain development, MeCP2 promotes the differentiation of neural stem cells into neurons and suppresses their differentiation into astrocytes, which normally support neuronal function. Furthermore, as a result of investigating this mechanism, it was found that MeCP2 regulates the differentiation of neural stem cells by suppressing bone morphogenetic protein (BMP) signaling, which is important for brain development, via a miRNA called miR-199a. In addition, brain organoids generated from iPS cells derived from Rett syndrome patients with MeCP2 gene mutations showed enhanced BMP signaling and increased differentiation into astrocytes, and it was revealed that these could be ameliorated by a BMP signal inhibitor. These results suggest that in the brains of Rett syndrome patients, the balance of differentiation from neural stem cells into neurons and astrocytes may not be properly regulated, and it is hoped that normalizing this balance will lead to the development of new therapies for Rett syndrome.
The results of this research were published in the international academic journal "Cell Reports" on Tuesday, May 18, 2021, at 11:00 a.m. (US Eastern Standard Time). This research was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT); the Japan Agency for Medical Research and Development (AMED); the Strategic Research Program for Brain Sciences; and the Rett Syndrome Support Organization.
For the full press release, please see below.