シンポジウム
23 哺乳類の脳の進化的拡大と複雑化
23 Evolutionary expansion and complication of the mammalian brain
座長：川口 綾乃（名古屋大学大学院医学系研究科）・河崎 洋志（金沢大学医学系） |
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| 2022年6月30日 14:00～14:20 ラグナガーデンホテル 羽衣：西 第10会場
1S10a-01
大脳皮質拡大に貢献する神経幹細胞outer radial gliaの誕生
Generation of outer radial glial cells that contribute to evolutionary expansion of the cerebral cortex
*川口 綾乃(1)
1. 名古屋大学大学院医学系研究科
*Ayano Kawaguchi(1)
1. Grad Sch Med, Nagoya Univ, Nagoya, Japan
Keyword: cerebral development, outer radial glia, basal radial glia
During neocortical development, many neuronally differentiating cells are generated at the apical/ventricular surface by the division of neural progenitor cells (apical radial glial cells, aRG). Outer radial glial cells (oRGs), also called basal radial glial cells (bRGs), are another type of undifferentiated neural progenitor cell: they have long radial fibers extending to the basal side, and their cell body exists in the SVZ. oRGs are first generated from aRGs, typically by oblique division at the apical surface, and they migrate to the SVZ without inheriting the apical structure.
In mice with lissencephalic brains, the number of oRGs is small, and their self-renewal potential in the SVZ is relatively limited. In contrast, in species with gyrencephalic brains, such as ferrets and primates, oRGs are more abundant and self-renew, producing many IPs and neurons. The unique cellular behaviors related to oRG generation, i.e., oblique division and mitotic somal translocation (MST), show evolutionary changes in their frequency and distance. Therefore elucidating the molecular mechanisms of oRG generation would contribute to understanding the evolutionary expansion of the mammalian cerebral cortex. We found that Lzts1, a key molecule of neurogenic cell delamination, also induces oRG generation by the oblique division of aRGs and MST.
The various cell departure patterns from the apical surface have been reported in lissencephalic and gyrencephalic developing brains. Interestingly, these diverse cellular behaviors appeared in response to the level of overexpressed Lzts1. In this talk, I would like to discuss that various cellular departure events might be understood as a continuous phenomenon linked to common molecular mechanisms, likely as a spectrum. | | 2022年6月30日 14:20～14:40 ラグナガーデンホテル 羽衣：西 第10会場
1S10a-02
神経幹細胞を育む外的要因
Extrinsic factors nurturing neural stem cells
*畠山 淳(1)、佐藤 晴香(1)、嶋村 健児(1)
1. 熊本大学発生医学研究所
*Jun Hatakeyama(1), Haruka Sato(1), Kenji Shimamura(1)
1. IMEG, Kumamoto Univ.
Keyword: neural stem cells, primates, cortical expansion, extrinsic factors
Primates including human have markedly expanded cerebral cortex. Expansion of the cerebral cortex is one of the important factors that archive higher cognitive abilities and sensorimotor functions. Recently, although intrinsic factors that support neural stem cells have uncovered in primates, contribution of extrinsic or environmental factors to the cortical expansion is unknown. Embryonic neural stem cells that reside in the luminal side of the neural tube are exposed to the cerebrospinal fluids (CSF) on their apical surface. CSF contains various secreting molecules, such as Shh, IGF and Wnt, each of which has been shown to be required for the proper growth of neural stem cells. In fact, slice culture of the cerebral cortex of mouse embryos can be maintained with 100% embryonic CSF but not with artificial CSF (Lahtinen MK et al.2011), indicating that CSF contains factors essential for the maintenance and proliferation of neural stem cells.We have identified several secreting factors in the embryonic CSF which are preferentially enriched in macaque monkey (Macaca fascicularis) compared to mouse. We found that these factors promoted proliferation of human neural stem cells, as well as murine ones. One of those factors could indeed induce cortical expansion in vivo, upon injection into the lateral ventricle of mouse embryos in utero. We would like to propose that these primate specific CSF factors play important roles in the expansion of cerebral cortex. CSF provides an optimal species-specific environment for nurturing neural stem cells. | | 2022年6月30日 14:40～15:05 ラグナガーデンホテル 羽衣：西 第10会場
1S10a-03
Exploring the relationship of progenitor subtypes in and between gyrencephalic species at the single cell level
*Fumio Matsuzaki(1), Yuji Tsunekawa(2,1), Merve Bilgic(3,1), Ikumi Fujita(1), Quan Wu(1), Atsunori Shitamukai(1), Taeko Suetsugu(1), Ayaka Omori(1), Nobuhisa Okada(1,5), Ryohei Tomita(1,4)
1. RIKEN Ctr for Biosystems Dynamics Research, Kobe, Japan, 2. Med Ins. Univ of Tokyo, Tokyo, Japan, 3. Grad Sch Pharm. Univ of Tokyo, Tokyo, Japan, 4. Grad Sch Biostudies, Kyoto Univ. Kyoto, Japan, 5. Grad Sch Med, Kyoto Univ. Kyoto, Japan
Keyword: brain development, ferret, human, single cell transcriptome
The expansion of the mammalian brain during evolution are thought to largely depend on the emergence of a new germinal layer (the outer subventricular zone: OSVZ) and great heterogeneity of progenitor cell types. As distinct subtypes of neural progenitors may generate different populations of progenies, it is crucial to characterize the spatial and temporal pattern of individual progenitor types and their terminal fates. in vivo genetic manipulation and single-cell transcriptome (scTCM) analyses are two powerful approaches to understand molecular and cellular properties of particular cells. scTCM of the human brain has been extensively performed, revealing transcriptional signatures of diverse progenitor populations. However, in vivo mechanisms underlying the development of human radial glial (RG) cells remained less explored due to a limited experimental access. Studies using brain organoids turned out to face problems to recapitulate molecular properties of cell-types in human brain development. Under this situation, a valuable animal model to overcome difficulties is the ferret (Mustela putorius furo), a carnivore with gyrencephalic features such as the OSVZ, forming a complex and folded brain, and also available for in utero electroporation (Kawasaki et al., 2012, Matsui et al., 2013) and de novo genome-editing (Tsunekawa et al., 2016). Yet, the temporal pattern of molecular signatures of ferret progenitors remained largely unexplored at a high resolution. We investigated progenitor subtypes in the ferret by scTCM along the developmental course, and compared them with human information to reveal common and species-specific cell-types during the development of the complex brain. We also manipulated progenitors in ferrets by several approaches to understand subtype relationships and fates of neural progenitors. | | 2022年6月30日 15:05～15:30 ラグナガーデンホテル 羽衣：西 第10会場
1S10a-04
フェレットを用いた大脳の肥大化と複雑化のメカニズムの解析
Investigation of the mechanisms underlying the expansion and complication of the cerebrum using ferrets
*河崎 洋志(1)
1. 金沢大学医学系
*Hiroshi Kawasaki(1)
1. Sch Med, Kanazawa Univ, Japan
Keyword: Cerebral cortex, Gyrus, Evolution, Ferret
The cerebrum has changed significantly during mammalian evolution. The cerebral cortex has become larger, and gyri were formed on the surface of the cerebral cortex. Furthermore, neuronal connections in the cerebrum have become complicated. At a cellular level, the number of neurons and astrocytes have markedly increased. Although these changes in the cerebrum during evolution have been considered to be important for the acquisition of higher brain functions, the mechanisms underlying the expansion and folding of the cerebral cortex remain unclear. Therefore, we utilized ferrets, which have relatively large and gyrencephalic cerebral cortex and established in utero electroporation techniques for ferrets in order to manipulate gene expressions in the ferret cerebral cortex. Furthermore, we found that gene knockout in the ferret cerebral cortex can be achieved by combining in utero electroporation and the CRISPR/Cas9 system. Using our techniques, we have found that fibroblast growth factor (FGF) signaling and sonic hedgehog (Shh) signaling are involved in cortical folding and expansion of neural progenitors in the developing ferret cerebral cortex. FGF signaling induces the proliferation of outer radial glial cells (oRG cells), whereas Shh signaling regulates the differentiation of oRG cells in the ferret cerebral cortex. We also identified a distinct subtype of neural progenitors, which seemed to be important for cortical folding. In this symposium, we will introduce our detailed functional analyses of the roles of FGF signaling and Shh signaling in the ferret cerebral cortex during development and will discuss their potential roles in the evolution of the cerebrum. Our technique for the ferret cerebral cortex should be useful for investigating the mechanisms underlying the development and evolution of the cerebral cortex. | | 2022年6月30日 15:30～16:00 ラグナガーデンホテル 羽衣：西 第10会場
1S10a-05
Neural stem cells, human-specific genes, and neocortex expansion in development and human evolution
*Wieland B Huttner(1)
1. Max Planck Institute of Molecular Cell Biology and Genetics
Keyword: Neural stem cells, Human-specific genes, Neocortex expansion, Human evolution
Two major classes of neural stem and progenitor cells (NPCs) in the developing neocortex can be distinguished. First, NPCs that reside in the ventricular zone (VZ), i.e. neuroepithelial cells, apical (or ventricular) radial glia (aRG), and apical intermediate progenitors, collectively referred to as apical progenitors (APs). Second, NPCs that reside in the subventricular zone (SVZ), i.e. basal (or outer) radial glia (bRG) and basal intermediate progenitors, collectively referred to as basal progenitors (BPs). Neocortex expansion is thought to be linked to an increased abundance and proliferative capacity of BPs.
The following topics will be addressed.
1. The role of the human-specific gene ARHGAP11B in BP amplification.
2. The finding that the ability of ARHGAP11B to amplify BPs is based on a single C-to-G base substitution.
3. The ability of ARHGAP11B to expand the neocortex of a non-human primate, the common marmoset.
4. The localization of ARHGAP11B in mitochondria of NPCs and its action to promote glutaminolysis, a metabolic pathway characteristic of cells with high proliferative capacity.
5. The finding that ARHGAP11B is necessary and sufficient to ensure human-type BP levels in primate cerebral organoids.
6. The increase in cognitive performance of ARHGAP11B-transgenic mice, which exhibit an expanded neocortex.
7. The increase in BP proliferative capacity due to the changes in their morphology in the course of neocortex evolution. | | | |
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