| 堅田 明子（かただ さやこ） | データ更新日：2023.11.28 |
講師 ／
医学研究院
応用幹細胞医科学部門
| 1. | ＠堅田明子、♯榊祐介、＠中島欽一, 脈絡叢分泌性miRNAによる成体海馬ニューロン新生の調節, 成体ニューロン懇親会, 2022.10. |
| 2. | ＠Sayako Katada, ♯Yusuke Sakaki, and ＠Kinichi Nakashima, miRNAs secreted from the choroid plexus modulates adult neurogenesis in the mouse hippocampus, Development and Plasticity of the Brain, 2022.10. |
| 3. | 堅田明子, 脈絡叢分泌性miRNAによる成体海馬ニューロン新生の調節, 繁殖生物学会, 2022.09. |
| 4. | ＠Sayako Katada, ♯Yusuke Sakaki, and ＠Kinichi Nakashima, miRNAs secreted from choroid plexus plays a critical role for the maintenance of neurogenesis in the aged brain, Neuro2022, 2022.06. |
| 5. | 堅田明子, 胎生期神経幹細胞はダイナミックにエピゲノム変換することで、発生時期に応じて適切な細胞へと分化する, 日本エピジェネティクス研究会年会, 2022.06, [URL]. |
| 6. | Sayako Katada, Molecular characterization of aging choroid plexus that regulates neural stem cell’s behavior and brain functions, 第43回日本分子生物学会年会, 2020.12, The choroid plexus (ChP), located in each brain ventricles, produces cerebrospinal fluid (CSF) and secretes various cytokines and growth factors into the CSF. Although several studies have reported that CSF serves as a niche for NSCs regulating neurogenesis, little is known about the aging changes. Since the ChP is sensitive to peripheral body signals, and gates immune cells to brain, disruption of ChP function and CSF composition are common to neurological disorders, such as multiple sclerosis, ischemia and Alzheimer`s disease. Despite these essential roles, remarkably little is known for the molecular mechanisms governing these functions of the ChP. Herein, we performed mRNA-seq analyses together with small RNA-seq of the ChP in the lateral ventricle using young (3-4 months) and aged (21-24 months) mice, and identified several sets of differentially expressed mRNA/miRNA. Global analysis of expressed genes in the lateral ventricle ChP cells revealed that the most overrepresented gene ontology terms in the aged mice are related to the inflammatory response. Indeed, single cell RNA-seq analysis clearly revealed that some population of aged ChP cells express higher level of chemokines such as Cxcl12/13 that linked to immune cell recruitment. In addition to the inflammatory response, several sets of ChP-expressed miRNA seemed to directly regulate NSCs proliferation. Taken together, our findings shed new light on the function of the ChP, and will facilitate future studies to design active and healthy brain barrier system.. |
| 7. | Sayako Katada, ＃Yusuke Sakaki, Rie Yamashita, Takuya Imamura and Kinichi Nakashima, Impact of structure and property changes of aging choroid plexus on neural stem cell regulation and brain functions, Keystone Symposia, 2020.02, Although neural stem cells (NSCs) produce new neurons even in adulthood, neurogenesis decreases in the brain with aging, and little is known about the underlying mechanisms. Several studies have reported that cerebrospinal fluid (CSF), which is primarily produced by the choroid plexus (ChP) in ventricles, serves as a niche for NSCs. ChP is a highly vascularized epithelial tissue constituting blood-CSF barrier and secretes various cytokines and growth factors into the CSF. We have recently performed mRNA-seq analyses together with small RNA-seq of the ChP in the lateral ventricle (LVChP) using young (3-4 months) and aged (21-24 months) mice, and identified several sets of differentially expressed mRNA/miRNA. Global analysis of expressed genes in the LVChP revealed that the most overrepresented gene ontology terms in the aged mice are related to the inflammatory response. Indeed, single cell RNA-seq analysis clearly revealed that some population of LVChP cells express higher level of chemokines such as Cxcl12/13 in aged mice. In addition to the inflammatory response, several sets of LVChP-expressed miRNA seemed to directly regulate NSCs proliferation. Taken together, our findings strongly suggest the potential of ChP in neural stem cells regulation and brain functions.. |
| 8. | Sayako Katada, Jun Takouda, Takumi Nakagawa, Mizuki Honda and Kinichi Nakashima, Developmental stage-dependent change of SMADs target genes define the neural stem cell fate, 第42回 日本分子生物学会, 2019.12, Neural stem cells (NSCs) are self-renewing, multipotent cells that generate neurons and glial cells such as astrocytes and oligodendrocytes. During brain development, tight regulation of neurogenesis to astrogenesis switching of NSCs is critical to generate a balanced number of each neural cell type for proper brain functions. Accumulating evidence has indicated that a complex array of epigenetic modifications control the timing of neuronal and astrocytic differentiation of NSCs, however, molecular mechanisms of NSC fate decision is still far from a complete understanding. Bone morphogenetic proteins (BMPs) are one group of well-characterized factors to induce astrocytic differentiation of NSCs. Nevertheless, we have recently found that BMPs induce neuronal differentiation of NSCs which were isolated from embryonic day 11 (E11). To elucidate molecular mechanism underlying developmental stage dependent change of NSCs fate in response to BMPs, we have performed genome-wide mapping of SMADs target genes in E11 and E14 of NSCs. RNA-seq and ChIP-seq analyses revealed that within this short developmental time period, SMADs dramatically change their targets, for example, SMADs specifically bound to the promoters of proneural genes, Neurog1 and Dlx2 in E11 but not in E14 NSCs. Conversely, SMADs binding on a typical astrocyte marker glial fibrillary acidic protein promoter was observed only in E14 NSCs. Mapping of these stage-specific SMADs binding regions with whole-genome bisulfite sequencing and ATAC-seq data, we identified several novel epigenetically regulated regions, which may contribute to the developmental stage-dependent alteration in the preference of NSC’s fate choice. . |
| 9. | Sayako Katada, Mizuki Honda, Kinichi Nakashima, Decoding mouse embryonic neural stem cell fate by BMP2 responsiveness, The 16th Stem Cell Research Symposium, 2018.06, [URL], In the developing mouse brain, the three major cell types, i.e., neurons and two glial cells (astrocytes and oligodendrocytes) are generated from common multipotent neural stem cells (NSCs). In this process, tight regulation of neurogenesis to astrogenesis switching of NSCs is critical to generate a balanced number of each neural cell type for proper brain functions. Accumulating evidence has indicated that a complex array of epigenetic modifications control the timing of neuronal and astrocytic differentiation of NSCs, however, molecular mechanisms of NSC fate decision is still far from complete understanding. Bone morphogenetic proteins (BMPs) are one group of well-characterized factors to induce astrocytic differentiation of NSCs obtained from mouse forebrain at relatively late-gestational stages (e.g., E14 and later). Nevertheless, we have recently found that BMPs induce neuronal differentiation of NSCs at mid-gestational stages (e.g., E11). To elucidate molecular mechanism underlying this developmental stage dependent change of NSCs fate in response to BMPs, we have performed genome-wide analyses of gene expression (RNA-seq), P-SMAD binding sites (ChIP-seq), and chromatin accessibility (ATAC-seq) in E11 and E14 NSCs. Comprehensive analyses revealed that within this short developmental time period, SMAD target genes were altered dramatically, contributing to the developmental stage-dependent alteration in the preference of NSC’s fate choice. . |
| 10. | Sayako Katada, Developmental stage-dependent change of SMAD target genes defines the neural stem cell fate, NCU Global Young Investigator forum, 2018.03. |
| 11. | Sayako Katada, Mizuki Honda, Jun Takouda, Katsuhide Igarashi, and Kinichi Nakashima, Developmental stage-dependent change of SMAD target genes defines the direction of neural stem cell differentiation induced by bone morphogenetic proteins, EMBO Conference Gene regulatory mechanisms in neural fate decision, 2017.09. |
| 12. | Sayako Katada, Implication of structure and functional changes of aging choroid plexus in neural stem cells regulation and brain functions, 2017.01. |
| 13. | Sayako Katada, 中枢神経系の発生・発達から老化までを制御する組織としての脈絡叢, 日本分子生物学会, 2015.12, [URL], 哺乳類の高次機能を支える脳組織は、発生過程において、神経幹細胞（NSC）がまず様々な種類のニューロンを産み出し、その後グリア細胞を順序だって産生、これらが定められた移動パターンを辿り、回路を形成することで構築される。ニューロンの多様性は、胚発生過程においてNSCが刻々と変化する時間、空間的な情報を感知し、分化運命を決定することにより成り立っている。成体脳においても側脳室周囲と海馬歯状回にはNSCが存在し、生涯を通じて新しいニューロンが生み出されている。これらは匂いの識別や学習・記憶に関わるが、加齢により新. |
| 14. | Sayako Katada, Mizuki Honda, Kinichi Nakashima, Oxygen regulates fate specification of neural stem cell during cortical development, Keystone Symposia:, 2015.02. |
| 15. | 堅田 明子, Impact of oxygen levels on fate switching of neural stem cell during corticogenesis, Neuro 2013, 2013.06, Oxygen (O2) is a substrate for energy production and deeply involved in the regulations of cellular metabolism. Although standard cell culture systems are exposed to the environmental O2 level of 21% (normoxia), actual O2 concentration in both developing and adult brains is 1-8% (hypoxia). Accumulating studies have revealed that O2 and its signal transduction pathways control cell proliferation, differentiation, and morphogenesis during the development of various tissues. The mammalian brain cortex comprises deep- and upper-layer neurons (layer V-VI and II-IV, respectively) and glial cells including astrocytes. All these cells are sequentially generated from common multipotent neural stem cells (NSCs) in this order during development. Therefore, NSCs at midgestation produce neither upper-layer neuron nor astrocyte, but mainly differentiate into deep-layer neurons. In addition, it is generally known that this NSC’s property change can be recapitulated in the embryonic stem (ES) cell culture systems. Recently, we have shown that the acquisition of astrogenic potential by NSCs is delayed in standard in vitro culture compared to those in vivo, while, in vitro culture under hypoxic condition can restore this impairment. Herein, we further analyze the impact of O2 levels during corticogenesis, i.e. deep- and upper-layer neuron production of NSCs. Mouse ES cells were cultured and induced to neural differentiation under normoxic or hypoxic condition, and the differentiation was evaluated by quantitative PCR and immunocytochemistry. We found that the expression of upper-layer specific neuronal genes in hypoxia culture appeared earlier than that in normoxia. Thus, it is conceivable that O2 levels contribute to appropriate scheduling of not only neuron-glia fate switching but also neuronal subtype specification throughout development.. |
| 16. | 堅田 明子, エピジェネティック修飾による時計遺伝子の発現制御機構, 第86回 日本生化学大会 , 2013.09, 脊椎動物における生物時計の発振では、bHLH/PAS型の転写因子であるCLOCKとBMAL1のヘテロ2量体が、時計遺伝子であるperiodやcryptochromeのプロモーター領域に結合することで転写が活性化される。これらの遺伝子産物であるPERおよびCRYは、CLOCK-BMAL1に直接作用し転写活性を抑制するため、自らの転写へのネガティブフィードバック機構が成立する。遺伝子の転写制御には、ヒストンタンパク質の修飾によるクロマチンリモデリングが密接に関与するが、近年、生物時計の発振においても、数多くの報告がされている。我々はまず、時計遺伝子プロモーター領域におけるヒストンH3K4のトリメチル化修飾に概日性のリズムがあること、またこのメチル化修飾のリズムが、ヒストンH3のアセチル化修飾と同調して生じることを発見した。さらに、ヒストンH3K4に特異的なメチル基転移酵素であるMLL1（mixed lineage leukemia 1）が、CLOCK-BMAL1と時間依存的に相互作用することを見出した。この時間依存的な相互作用により、 MLL1はCLOCK-BMAL1と伴に標的遺伝子のプロモーターへとリクルートされ、その領域でのヒストンH3K4のトリメチル化修飾を行う。この結果生じるクロマチン構造変化は、MLL1-pol II・CLOCK-BMAL1を含む転写関連因子群のプロモーターへの結合を安定化させ、標的遺伝子の転写活性を促進することを明らかにした。すなわち、MLL1はクロマチンリモデリングにより、時計発振に必須な転写因子がDNAに結合するための場の制御を行う。本講演では、堅調に概日性の周期を刻むため生物が獲得した、さまざまなエピジェネティック制御について紹介する。. |
| 17. | 本田瑞希, 堅田 明子, 中島 欽一, 胎生期マウス神経幹細胞の増殖・分化制御に関与するPRMT の同定とその機能解析, 神経発生討論会, 2014.03. |
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