Language：English   Publisher：Stem Cell Reports  

Although microglia are macrophages of the central nervous system, their involvement is not limited to immune functions. The roles of microglia during development in humans remain poorly understood due to limited access to fetal tissue. To understand how microglia can impact human neurodevelopment, the methyl-CpG binding protein 2 (MECP2) gene was knocked out in human microglia-like cells (MGLs). Disruption of the MECP2 in MGLs led to transcriptional and functional perturbations, including impaired phagocytosis. The co-culture of healthy MGLs with MECP2-knockout (KO) neurons rescued synaptogenesis defects, suggesting a microglial role in synapse formation. A targeted drug screening identified ADH-503, a CD11b agonist, restored phagocytosis and synapse formation in spheroid-MGL co-cultures, significantly improved disease progression, and increased survival in MeCP2-null mice. These results unveil a MECP2-specific regulation of human microglial phagocytosis and identify a novel therapeutic treatment for MECP2-related conditions.

DOI： 10.1016/j.stemcr.2024.06.013

Scopus

PubMed

Language：English   Publisher：Epigenomes  

The development of the nervous system is regulated by numerous intracellular molecules and cellular signals that interact temporally and spatially with the extracellular microenvironment. The three major cell types in the brain, i.e., neurons and two types of glial cells (astrocytes and oligodendrocytes), are generated from common multipotent neural stem cells (NSCs) throughout life. However, NSCs do not have this multipotentiality from the beginning. During cortical development, NSCs sequentially obtain abilities to differentiate into neurons and glial cells in response to combinations of spatiotemporally modulated cell-intrinsic epigenetic alterations and extrinsic factors. After the completion of brain development, a limited population of NSCs remains in the adult brain and continues to produce neurons (adult neurogenesis), thus contributing to learning and memory. Many biological aspects of brain development and adult neurogenesis are regulated by epigenetic changes via behavioral control of NSCs. Epigenetic dysregulation has also been implicated in the pathogenesis of various brain diseases. Here, we present recent advances in the epigenetic regulation of NSC behavior and its dysregulation in brain disorders.

DOI： 10.3390/epigenomes8020022

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Epilepsy is a chronic neurological disorder characterized by hypersynchronous spontaneous recurrent seizures, and affects approximately 50 million people worldwide. Cumulative evidence has revealed that epileptogenic insult temporarily increases neurogenesis in the hippocampus; however, a fraction of the newly generated neurons are integrated abnormally into the existing neural circuits. The abnormal neurogenesis, including ectopic localization of newborn neurons in the hilus, formation of abnormal basal dendrites, and disorganization of the apical dendrites, rewires hippocampal neural networks and leads to the development of spontaneous seizures. The central roles of hilar ectopic granule cells in regulating hippocampal excitability have been suggested. In this review, we introduce recent findings about the migration of newborn granule cells to the dentate hilus after seizures and the roles of seizure-induced ectopic granule cells in the epileptic brain. In addition, we delineate possible intrinsic and extrinsic mechanisms underlying this abnormality. Finally, we suggest that the regulation of seizure-induced ectopic cells can be a promising target for epilepsy therapy and provide perspectives on future research directions.

DOI： 10.3389/fnins.2023.1150283

Web of Science

Scopus

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： https://doi.org/10.3389/fnins.2023.1150283

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1172/jci.insight.139171

Language：Japanese  

Language：Others  

Language：Others  

Language：Others  

Language：Others  

Event date： 2024.3

Language：Japanese  

Country：Japan  

Event date： 2024.2

Language：Japanese  

Country：Japan  

Event date： 2023.11

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2023.10

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Language：Japanese   Publisher：(株)ニュー・サイエンス社  

MECP2遺伝子変異は,Rett症候群(RTT)をはじめ,自閉症,統合失調症などを含めた様々な精神疾患・発達障害への関与が知られいるが,その発症機序の詳細は不明である。これまで,MECP2変異によるニューロンの機能異常がRTT発症の原因と考えられてきたが,近年グリア細胞の機能異常もRTT病態発症の重要な一因であることが示唆され始めている。筆者らは,RTT病態が発症する以前の生後1日目のMeCP2欠損マウス脳において,既にアストロサイトの遺伝子発現に変化が起きており,特にニューロンの発達に関連する遺伝子群が異常発現していることを突き止めた。そこで,RTT病態発症に関与するアストロサイト機能性分子を同定し,そのシグナル異常メカニズムを明らかにすることで,発症原因に基づいた効果的な神経発達障害の治療法開発を目指す。(著者抄録)

Language：Japanese   Publisher：(公財)金原一郎記念医学医療振興財団  

＜文献概要＞ヒトの個性はどのようにして決まるのだろうか。われわれヒトを含む生物は,遺伝子情報に基づいてその生命体を構成・維持している。しかし,ヒトの個性を決めるのは単に遺伝子情報だけではない。がん家系に生まれた人でも,お酒やたばこを控えるなど周囲の環境を改善することでがんにならずに済む人もいる。近年,われわれの体を構成する細胞には,DNAの配列変化を伴わずに,遺伝子発現の強弱あるいはオン/オフを制御するしくみが存在しており,その制御は環境要因によって動的に変化することが科学的に明らかになってきた。この制御を"エピジェネティクス"と呼び,遺伝子配列情報だけでは理解できない事象を理解するために非常に重要である。本稿ではエピジェネティクスの概要と,それが生み出すと考えられる個性について紹介する。

Audience： General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience： General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Other