前年度優秀賞受賞者企画シンポジウム「次世代研究者による脳発達・再生への挑戦」
Symposium Organized by the Recipient of the 2019 JSN Distinguished Investigator Award |
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| 2020/9/11 9:00～9:25 Zoom A
AS-01
脳発生におけるニューロン移動開始の鍵分子Lzts1の機能からみる大脳組織形成の仕組み
Histogenesis of the cerebral cortex by Lzts1, a master modulator of neuronal delamination
*川口 綾乃1
1. 名古屋大学大学院医学系研究科 細胞生物学分野
*Ayano Kawaguchi1
1. Dept of Anatomy and Cell Biology, Grad Sch of Med, Nagoya Univ.
During cerebral development, apical radial glial cells (aRGs) divide at the apical/ventricular surface to produce two daughter cells. Once the daughter cells are committed to differentiate into the neuronal lineage, they must migrate from the apical surface to place the neurons at their final location in the neuronal layers. Neuronal delamination from the apical surface is the first step of the neuronal migration and is essential for the formation of the 3-dimensional, organized architecture.
Recently, we have found that the microtubule-associated protein Lzts1 positively controls the neuronal delamination. Young neuronally-differentiating cells express Lzts1 at the adherens junction of their apical processes, and Lzt1 alters the apical junction organization through activation of the actomyosin system to induce delamination. Interestingly, Lzts1 is also involved in the generation of another type of neural progenitor cells, i.e., outer radial glial cells (oRGs), by inducing the oblique division of aRGs and mitotic somal translocation (MST). oRGs are undifferentiated neural progenitor cells that divide multiple times in the subventricular zone (SVZ). They are more abundant and proliferative in the species with gyrencephalic brains, such as humans, than in mice with lissencephalic brains.
Our findings suggest that neuronal delamination and oRG generation, the two major cell behaviors for departure from the apical surface, are two aspects of the same process, continuously variable cellular dynamics controlled by Lzts1. In this talk, I would like to discuss our model in which Lzts1 expression-levels modulate the various cellular behaviors and how it contributes to the histogenesis of the cerebral cortex during development.
| | 2020/9/11 9:25～9:50 Zoom A
AS-02
多彩な細胞現象の協調作用による神経細胞の移動と成熟の制御
Multiple cellular events cooperatively regulate neuronal migration and maturation
*川内 健史1,2
1. 神戸医療産業都市推進機構 先端医療研究センター 老化機構研究部、2. 慶應義塾大学医学部 生理学教室
*Takeshi kawauchi1,2
1. Department of Gerontology, Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation, 2. Department of Physiology, Keio University School of Medicine
During cerebral cortical development, post-mitotic neurons, generated near the ventricle, undergo multi-step migration and maturation. Defects in neuronal migration and maturation are associated with several neurological disorders. We have previously reported that microtubule and actin cytoskeletal organization are essential for proper neuronal migration. We also found that endocytosis-mediated regulation of cell adhesion molecules, N-cadherin and L1-CAM, and extra-cell cycle regulatory function of cell cycle proteins play important roles in the neuronal migration and maturation. These findings indicate that various cellular events, such as cytoskeletal organization, cell adhesion, membrane trafficking and cell cycle events, are involved in the neuronal migration and maturation during the development of cerebral cortex. In addition, although it has been controversial whether clathrin-independent endocytosis is required for a physiological process or just an artifact in vitro, our recent data reveal that clathrin-dependent and -independent endocytic pathways differentially regulate cerebral cortical development. In this symposium, I will overview various aspects of molecular and cellular mechanisms underlying cortical neuronal migration and maturation.
| | 2020/9/11 9:50～10:15 Zoom A
AS-03
ミクログリアからニューロンへのダイレクトリプログラミングによる脳梗塞治療
Direct neuronal conversion of microglia reinstates neurological function after ischemic injury
*松田 泰斗1、中島 欽一1
1. 九州大学
*Taito Matsuda1, Kinichi Nakashima1
1. Kyushu University
Ischemic brain injury causes permanent neuronal loss, which often results in persistent severe neurological dysfunctions. Although generating new neurons in the injured brain would be an ideal approach to replenish the lost neurons for repairing the damage, the adult mammalian brain retains only limited neurogenic capability. We have recently shown that brain-resident immune cells, microglia, can be directly converted into neurons by expressing the single transcription factor NeuroD1 both in vitro and in the mouse brain. Here, we show that direct conversion of microglia into neurons in the brain has great potential as a therapeutic strategy for ischemic brain injury. After transient middle cerebral artery occlusion (tMCAO) in adult mice, microglia converge at the lesion core of the striatum, where neuronal loss is prominent. Targeted expression of a neurogenic transcription factor, NeuroD1, in microglia in the injured striatum enables their conversion into induced neuronal (iN) cells that functionally integrate into the existing neuronal circuits. Furthermore, NeuroD1-mediated iN cell generation significantly improves neurological function of the tMCAO model mice, and the ablation of iN cells abolishes the gained functional recovery. Our findings thus demonstrate that neuronal conversion contributes directly to functional recovery after tMCAO and shed further light on the development of therapies for ischemic brain injury by in situ neuronal conversion technology.
| | 2020/9/11 10:15～10:40 Zoom A
AS-04
脳梗塞後の新生ニューロンの移動と神経回路の再生
Migration and functional integration of new neurons in the post-stroke brain
*金子 奈穂子1,2、澤本 和延1,2
1. 名古屋市立大学、2. 生理学研究所
*Naoko Kaneko1,2, Kazunobu Sawamoto1,2
1. Nagoya City University, 2. National Institute for Physiological Sciences
New neurons are continuously generated in the ventricular-subventricular zone (V-SVZ) located at the lateral walls of the lateral ventricles in the postnatal mammalian brain. The newly generated immature neurons are highly motile. Under physiological conditions, they migrate toward the olfactory bulb, where they differentiate into olfactory interneurons. After ischemic stroke, some of the new neurons migrate toward the injured areas. However, the ability of the mammalian brain to regenerate neuronal circuits is quite limited. We are studying the mechanisms of neuronal regeneration using a mouse model of ischemic stroke. Within a few days after stroke, astrocytes in and around the damaged area are activated, which develop hypertrophic morphology with a large soma and many thick processes. Time-lapse imaging of post-stroke brain slices indicated that the new neurons could not efficiently migrate through the meshwork of these astrocytes. The migrating new neurons use Slit1-Robo2 signaling to disrupt the actin cytoskeleton in activated astrocytes at the site of contact. Slit1 overexpression in new neurons transplanted into the post-stroke brain could promote their migration, leading to an increase in the proportion of mature new neurons distributed close to the injured area compared with the control group. The Slit1-overexpression enhanced the axonal projection of these new neurons to the target area of the lateral striatal neurons that had been lost after stroke. Furthermore, the Slit1-overexpression in new neurons resulted in neurological improvement over 10 weeks after stroke. These results suggest that the controlling migration of new neurons is critical for efficient neuronal regeneration in cell-based therapies for brain injury.
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