記述言語：英語   掲載種別：研究論文（学術雑誌）  

The PRC2 (Polycomb repressive complex 2) complex is a multi-component histone H3K27 methyltransferase, best known for silencing Hox genes during embryonic development. The Polycomb-like proteins PHF1, MTF2 and PHF19 are critical components of PRC2 by stimulating its catalytic activity in embryonic stem (ES) cells. The Tudor domains of PHF1/19 have been previously shown to be readers of H3K36me3 in vitro. However, some other studies suggest that PHF1 and PHF19 co-localize with the H3K27me3 mark, but not H3K36me3 in cells. Here, we provide further evidence that PHF1 co-localizes with H3t in testis, and its Tudor domain preferentially binds to H3tK27me3 over canonical H3K27me3 in vitro. Our complex structures of the Tudor domains of PHF1 and PHF19 with H3tK27me3 shed light on the molecular basis for preferential recognition of H3tK27me3 by PHF1 and PHF19 over canonical H3K27me3, implicating that H3tK27me3 might be a physiological ligand of PHF1/19.

DOI： 10.7554/eLife.58675

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer New York LLC  

DOI： 10.1007/s10815-017-1061-9

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0188051

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

添付ファイル： Ueda, J., et al., Cell Reports, 2017.pdf

DOI： 10.1016/j.celrep.2016.12.065

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

添付ファイル： Ho et al., Histology and Histopathology, 2016.pdf

DOI： 10.14670/HH-11-665

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1128/MCB.00099-14

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

添付ファイル： Ueda, J., et al., Stem Cell Reports, 2014.pdf

DOI： 10.1016/j.stemcr.2014.05.008

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1101/gad.221176.113

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担当区分：最終著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/dgd.12048

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

In serum, mouse embryonic stem cells (mESCs) fluctuate between a naive inner cell mass (ICM)-like state and a primed epiblast-like state, but when cultured with inhibitors of the mitogen-activated protein kinase (MAPK) and glycogen synthase kinase 3 pathways (2i), they are harnessed exclusively in a distinct naive pluropotent state, the ground state, that more faithfully recapitulates the ICM. Understanding the mechanism underlying this naive pluripotent state will be critical for realizing the full potential of ESCs. We show here that PRDM14, a PR-domain-containing transcriptional regulator, ensures naive pluripotency through a dual mechanism: antagonizing activation of the fibroblast growth factor receptor (FGFR) signaling by the core pluripotency transcriptional circuitry, and repressing expression of de novo DNA methyltransferases that modify the epigenome to a primed epiblast-like state. PRDM14 exerts these effects by recruiting polycomb repressive complex 2 (PRC2) specifically to key targets and repressing their expression.

DOI： 10.1016/j.stem.2012.12.012

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

添付ファイル： Yamagata, K., Ueda, J., et al., Dev. Biol., 2010.pdf

DOI： 10.1016/j.ydbio.2010.07.021

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

添付ファイル： Ueda, J., et al., J. Biol. Chem., 2006.pdf

DOI： 10.1074/jbc.M603087200

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Transcriptional response to changes in oxygen concentration is mainly controlled by hypoxia-inducible transcription factors (HIFs). Besides regulation of hypoxia-responsible gene expression, HIF-3α has recently been shown to be involved in lung development and in the metabolic process of fat tissue. However, the precise mechanism for such properties of HIF-3α is still largely unknown. To this end, we generated HIF3A gene-disrupted mice by means of genome editing technology to explore the pleiotropic role of HIF-3α in development and physiology. We obtained adult mice carrying homozygous HIF3A gene mutations with comparable body weight and height to wild-type mice. However, the number of litters and ratio of homozygous mutation carriers born from the mating between homozygous mutant mice was lower than expected due to sporadic deaths on postnatal day 1. HIF3A gene-disrupted mice exhibited abnormal configuration of the lung such as a reduced number of alveoli and thickened alveolar walls. Transcriptome analysis showed, as well as genes associated with lung development, an upregulation of stearoyl-Coenzyme A desaturase 1, a pivotal enzyme for fatty acid metabolism. Analysis of fatty acid composition in the lung employing gas chromatography indicated an elevation in palmitoleic acid and a reduction in oleic acid, suggesting an imbalance in distribution of fatty acid, a constituent of lung surfactant. Accordingly, administration of glucocorticoid injections during pregnancy resulted in a restoration of normal alveolar counts and a decrease in neonatal mortality. In conclusion, these observations provide novel insights into a pivotal role of HIF-3α in the preservation of critically important structure and function of alveoli beyond the regulation of hypoxia-mediated gene expression.

DOI： 10.1371/journal.pone.0300751

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Mutations in GNAS drive pancreatic tumorigenesis and frequently occur in intraductal papillary mucinous neoplasm (IPMN); however, their value as a therapeutic target is yet to be determined. This study aimed at evaluating the involvement of mutant GNAS in tumor aggressiveness in established pancreatic cancer. METHODS: CRISPR/Cas9-mediated GNAS R201H silencing was performed using human primary IPMN-associated pancreatic cancer cells. The role of oncogenic GNAS in tumor maintenance was evaluated by conducting cell culture and xenograft experiments, and western blotting and transcriptome analyses were performed to uncover GNAS-driven signatures. RESULTS: Xenografts of GNAS wild-type cells were characterized by a higher Ki-67 labeling index relative to GNAS-mutant cells. Phenotypic alterations in the GNAS wild-type tumors resulted in a significant reduction in mucin production accompanied by solid with massive stromal components. Transcriptional profiling suggested an apparent conflict of mutant GNAS with KRAS signaling. A significantly higher Notch intercellular domain (NICD) was observed in the nuclear fraction of GNAS wild-type cells. Meanwhile, inhibition of protein kinase A (PKA) induced NICD in GNAS-mutant IPMN cells, suggesting that NOTCH signaling is negatively regulated by the GNAS-PKA pathway. GNAS wild-type cells were characterized by a significant invasive property relative to GNAS-mutant cells, which was mediated through the NOTCH regulatory pathway. CONCLUSIONS: Oncogenic GNAS induces mucin production, not only via MUC2 but also via MUC5AC/B, which may enlarge cystic lesions in the pancreas. The mutation may also limit tumor aggressiveness by attenuating NOTCH signaling; therefore, such tumor-suppressing effects must be considered when therapeutically inhibiting the GNAS pathway.

DOI： 10.1007/s00535-021-01846-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cellular repressor of E1A-stimulated genes 1 (CREG1) is a secreted glycoprotein that accelerates p16-dependent cellular senescence in vitro. We recently reported the ability of CREG1 to stimulate brown adipogenesis using adipocyte P2-CREG1-transgenic (Tg) mice; however, little is known about the effect of CREG1 on aging-associated phenotypes. In this study, we investigated the effects of CREG1 on age-related obesity and renal dysfunction in Tg mice. Increased brown fat formation was detected in aged Tg mice, in which age-associated metabolic phenotypes such as body weight gain and increases in blood glucose were improved compared with those in wild-type (WT) mice. Blood CREG1 levels increased significantly in WT mice with age, whereas the age-related increase was suppressed, and its levels were reduced, in the livers and kidneys of Tg mice relative to those in WT mice at 25 months. Intriguingly, the mRNA levels of Ink4a, Arf, and senescence-associated secretory phenotype (SASP)-related genes and p38MAPK activity were significantly lowered in the aged kidneys of Tg mice, in which the morphological abnormalities of glomeruli as well as filtering function seen in WT kidneys were alleviated. These results suggest the involvement of CREG1 in kidney aging and its potential as a target for improving age-related renal dysfunction.

DOI： 10.3390/ijms22031276

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Stimulator of interferon genes (STING) contributes to anti-tumor immunity by activating antigen-presenting cells and inducing mobilization of tumor-specific T cells. A role for tumor-migrating neutrophils in the anti-tumor effect of STING-activating therapy has not been defined. We used mouse tumor transplantation models for assessing neutrophil migration into the tumor triggered by intratumoral treatment with STING agonist, 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). Intratumoral STING activation with cGAMP enhanced neutrophil migration into the tumor in an NF-κB/CXCL1/2-dependent manner. Blocking the neutrophil migration by anti-CXCR2 monoclonal antibody impaired T cell activation in tumor-draining lymph nodes (dLNs) and efficacy of intratumoral cGAMP treatment. Moreover, the intratumoral cGAMP treatment did not show any anti-tumor effect in type I interferon (IFN) signal-impaired mice in spite of enhanced neutrophil accumulation in the tumor. These results suggest that both neutrophil migration and type I interferon (IFN) induction by intratumoral cGAMP treatment were critical for T-cell activation of dLNs and the anti-tumor effect. In addition, we also performed in vitro analysis showing enhanced cytotoxicity of neutrophils by IFN-β1. Extrinsic STING activation triggers anti-tumor immune responses by recruiting and activating neutrophils in the tumor via two signaling pathways, CXCL1/2 and type I IFNs.

DOI： 10.1007/s00262-021-02864-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Cell-free DNA (cfDNA) shed from tumors into the circulation offers a tool for cancer detection. Here, we evaluated the feasibility of cfDNA measurement and utility of digital PCR (dPCR)-based assays, which reduce subsampling error, for diagnosing pancreatic ductal adenocarcinoma (PDA) and surveillance of intraductal papillary mucinous neoplasm (IPMN). METHODS: We collected plasma from seven institutions for cfDNA measurements. Hot-spot mutations in KRAS and GNAS in the cfDNA from patients with PDA (n = 96), undergoing surveillance for IPMN (n = 112), and normal controls (n = 76) were evaluated using pre-amplification dPCR. RESULTS: Upon Qubit measurement and copy number assessment of hemoglobin-subunit (HBB) and mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1 (MT-ND1) in plasma cfDNA, HBB offered the best resolution between patients with PDA relative to healthy subjects [area under the curve (AUC) 0.862], whereas MT-ND1 revealed significant differences between IPMN and controls (AUC 0.851). DPCR utilizing pre-amplification cfDNA afforded accurate tumor-derived mutant KRAS detection in plasma in resectable PDA (AUC 0.861-0.876) and improved post-resection recurrence prediction [hazard ratio (HR) 3.179, 95% confidence interval (CI) 1.025-9.859] over that for the marker CA19-9 (HR 1.464; 95% CI 0.674-3.181). Capturing KRAS and GNAS could also provide genetic evidence in patients with IPMN-associated PDA and undergoing pancreatic surveillance. CONCLUSIONS: Plasma cfDNA quantification by distinct measurements is useful to predict tumor burden. Through appropriate methods, dPCR-mediated mutation detection in patients with localized PDA and IPMN likely to progress to invasive carcinoma is feasible and complements conventional biomarkers.

DOI： 10.1007/s00535-020-01724-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Osteoclasts are hematopoietic-derived cells that resorb bone. They are required to maintain proper bone homeostasis and skeletal strength. Although osteoclast differentiation depends on receptor activator of NF-κB ligand (RANKL) stimulation, additional molecules further contribute to osteoclast maturation. Here, we demonstrate that protocadherin-7 (Pcdh7) regulates formation of multinucleated osteoclasts and contributes to maintenance of bone homeostasis. We found that Pcdh7 expression is induced by RANKL stimulation, and that RNAi-mediated knockdown of Pcdh7 resulted in impaired formation of osteoclasts. We generated Pcdh7-deficient mice and found increased bone mass due to decreased bone resorption but without any defect in bone formation. Using an in vitro culture system, it was revealed that formation of multinucleated osteoclasts is impaired in Pcdh7-deficient cultures, while no apparent defects were observed in differentiation and function of Pcdh7-deficient osteoblasts. Taken together, these results reveal an osteoclast cell-intrinsic role for Pcdh7 in maintaining bone homeostasis.

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.theriogenology.2020.01.006

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41413-019-0080-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Background: Animal model studies show that reductive stress is involved in cardiomyopathy and myopathy, but the exact physiological relevance remains unknown. In addition, the microRNAs miR-143 and miR-145 have been shown to be upregulated in cardiac diseases, but the underlying mechanisms associated with these regulators have yet to be explored. Methods: We developed transgenic mouse lines expressing exogenous miR-143 and miR-145 under the control of the alpha-myosin heavy chain (αMHC) promoter/enhancer. Results: The two transgenic lines showed dilated cardiomyopathy-like characteristics and early lethality with markedly increased expression of miR-143. The expression of hexokinase 2 (HK2), a cardioprotective gene that is a target of miR-143, was strongly suppressed in the transgenic hearts, but the in vitro HK activity and adenosine triphosphate (ATP) content were comparable to those observed in wild-type mice. In addition, transgenic complementation of HK2 expression did not reduce mortality rates. Although HK2 is crucial for the pentose phosphate pathway (PPP) and glycolysis, the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) was unexpectedly higher in the hearts of transgenic mice. The expression of gamma-glutamylcysteine synthetase heavy subunit (γ-GCSc) and the in vitro activity of glutathione reductase (GR) were also higher, suggesting that the recycling of GSH and its de novo biosynthesis were augmented in transgenic hearts. Furthermore, the expression levels of glucose-6-phosphate dehydrogenase (G6PD, a rate-limiting enzyme for the PPP) and p62/SQSTM1 (a potent inducer of glycolysis and glutathione production) were elevated, while p62/SQSTM1 was upregulated at the mRNA level rather than as a result of autophagy inhibition. Consistent with this observation, nuclear factor erythroid-2 related factor 2 (Nrf2), Jun N-terminal kinase (JNK) and inositol-requiring enzyme 1 alpha (IRE1α) were activated, all of which are known to induce p62/SQSTM1 expression. Conclusions: Overexpression of miR-143 and miR-145 leads to a unique dilated cardiomyopathy phenotype with a reductive redox shift despite marked downregulation of HK2 expression. Reductive stress may be involved in a wider range of cardiomyopathies than previously thought.

DOI： 10.1186/s11658-020-00232-x

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その他リンク： http://link.springer.com/article/10.1186/s11658-020-00232-x/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0220199

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND & AIMS: Intraductal papillary mucinous neoplasms (IPMNs) are regarded as precursors of pancreatic ductal adenocarcinomas (PDAs), but little is known about the mechanism of progression. This makes it challenging to assess cancer risk in patients with IPMNs. We investigated associations of IPMNs with concurrent PDAs by genetic and histologic analyses. METHODS: We obtained 30 pancreatic tissues with concurrent PDAs and IPMNs, and 168 lesions, including incipient foci, were mapped, microdissected, and analyzed for mutations in 18 pancreatic cancer-associated genes and expression of tumor suppressors. RESULTS: We determined the clonal relatedness of lesions, based on driver mutations shared by PDAs and concurrent IPMNs, and classified the lesions into 3 subtypes. Twelve PDAs contained driver mutations shared by all concurrent IPMNs, which we called the sequential subtype. This subset was characterized by less diversity in incipient foci with frequent GNAS mutations. Eleven PDAs contained some driver mutations that were shared with concurrent IPMNs, which we called the branch-off subtype. In this subtype, PDAs and IPMNs had identical KRAS mutations but different GNAS mutations, although the lesions were adjacent. Whole-exome sequencing and methylation analysis of these lesions indicated clonal origin with later divergence. Ten PDAs had driver mutations not found in concurrent IPMNs, called the de novo subtype. Expression profiles of TP53 and SMAD4 increased our ability to differentiate these subtypes compared with sequencing data alone. The branch-off and de novo subtypes had substantial heterogeneity among early clones, such as differences in KRAS mutations. Patients with PDAs of the branch-off subtype had a longer times of disease-free survival than patients with PDAs of the de novo or the sequential subtypes. CONCLUSIONS: Detailed histologic and genetic analysis of PDAs and concurrent IPMNs identified 3 different pathways by which IPMNs progress to PDAs-we call these the sequential, branch-off, and de novo subtypes. Subtypes might be associated with clinical and pathologic features and be used to select surveillance programs for patients with IPMNs.

DOI： 10.1053/j.gastro.2018.10.029

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-018-31975-5

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その他リンク： http://www.nature.com/articles/s41598-018-31975-5

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/nar/gkx475

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Uhrf1-dependent histone H3 ubiquitylation plays a crucial role in the maintenance of DNA methylation via the recruitment of the DNA methyltransferase Dnmt1 to DNA methylation sites. However, the involvement of deubiquitylating enzymes (DUBs) targeting ubiquitylated histone H3 in the maintenance of DNA methylation is largely unknown. With the use of Xenopus egg extracts, we demonstrate here that Usp7, a ubiquitin carboxyl-terminal hydrolase, forms a stable complex with Dnmt1 and is recruited to DNA methylation sites during DNA replication. Usp7 deubiquitylates ubiquitylated histone H3 in vitro. Inhibition of Usp7 activity or its depletion in egg extracts results in enhanced and extended binding of Dnmt1 to chromatin, suppressing DNA methylation. Depletion of Usp7 in HeLa cells causes enhanced histone H3 ubiquitylation and enlargement of Dnmt1 nuclear foci during DNA replication. Our results thus suggest that Usp7 is a key factor that regulates maintenance of DNA methylation.

DOI： 10.1038/s41598-017-00136-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jmb.2016.08.010

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/srep02436

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Association for the Advancement of Science  

DOI： 10.1126/science.1237999

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/stem.1119

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/nsmb.1476

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1365-2443.2007.01098.x

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記述言語：日本語   掲載種別：学位論文（博士）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1101/gad.1284005

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1101/gad989402

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

添付ファイル： 日経バイオテク.pdf

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

添付ファイル： 日経新聞記事.pdf

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

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担当区分：筆頭著者,　責任著者   掲載種別：記事・総説・解説・論説等（学術雑誌）  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

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添付ファイル： プレスリリース_旭川医大・基生研_最終版NIBB.pdf

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記述言語：日本語   出版者・発行元：東京 : 北隆館  

CiNii Books

CiNii Research

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

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担当区分：最終著者   記述言語：英語   掲載種別：記事・総説・解説・論説等（国際会議プロシーディングズ）   出版者・発行元：IEEE  

DOI： 10.1109/iiai-aai50415.2020.00099

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記述言語：英語   掲載種別：記事・総説・解説・論説等（国際会議プロシーディングズ）   出版者・発行元：Springer International Publishing  

DOI： 10.1007/978-3-030-25213-7_13

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記述言語：英語   掲載種別：記事・総説・解説・論説等（国際会議プロシーディングズ）   出版者・発行元：IEEE  

DOI： 10.1109/iiai-aai.2019.00123

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担当区分：最終著者   記述言語：英語   掲載種別：記事・総説・解説・論説等（国際会議プロシーディングズ）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.procs.2019.09.318

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

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記述言語：日本語   出版者・発行元：東京 : 北隆館  

CiNii Books

CiNii Research

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その他リンク： http://id.ndl.go.jp/bib/030214937

記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

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記述言語：日本語  

J-GLOBAL

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

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J-GLOBAL

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生きたままメチル化DNAを可視化することが出来る「MethylRO」マウス由来の胚性幹細胞を用いて、イメージング条件下で単一細胞状態からエピブラスト様細胞に分化・分裂誘導が可能な系の構築について概説する

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Scopus

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記述言語：日本語  

J-GLOBAL

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

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記述言語：英語   掲載種別：記事・総説・解説・論説等（国際会議プロシーディングズ）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.procs.2017.08.255

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J-GLOBAL

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J-GLOBAL

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（大学・研究所紀要）  

添付ファイル： L01_012_073.pdf

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（大学・研究所紀要）  

添付ファイル： L01_012_092.pdf

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記述言語：英語   掲載種別：記事・総説・解説・論説等（国際会議プロシーディングズ）  

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J-GLOBAL

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

DOI： 10.1274/jmor.32.149

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記述言語：日本語  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

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記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

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記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）  

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記述言語：日本語   掲載種別：会議報告等  

添付ファイル： NewsNo32.pdf

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

Web of Science

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

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記述言語：日本語   出版者・発行元：日本繁殖生物学会  

【目的】ES細胞は胚盤胞期胚の内部細胞塊に由来する。しかし，全ての胚から必ず樹立できるわけではなく、その過程には不明な点が多い。元来、樹立は培養環境に大きく作用される「デリケート」なプロセスと思われており，これまでその過程については詳細に観察されてこなかった。そこで，以前にわれわれが開発した「細胞にやさしい」ライブセルイメージング技術を用いて，初期胚からES細胞が樹立される過程の連続観察を行った。【方法】Oct3/4遺伝子プロモーター下流にEGFP遺伝子をつないだコンストラクトで作製したトランスジェニックマウス（Ohno et al., 2003）をリポーターに用いた。自然交配で得られた桑実期胚をガラスボトムディッシュ中のフィーダー細胞上に乗せた。それらをイメージング顕微鏡のインキュベータチャンバーに移し，10日間の蛍光4次元観察を行った。樹立されたES様細胞は継代し，キメラマウスの作製を行なうことで多分化能を確認した。【結果】桑実期胚では全ての割球がOct3/4陽性であったが，内腔を生じ十分に膨らんだ胚盤胞期胚では栄養外胚葉でのシグナルが徐々に減弱し，結果的に内部細胞塊にのみシグナルが見られた。その後，栄養外胚葉の細胞は大規模なアポトーシスを起こし消失した。ここまでは比較的どの胚でも同じであったが，これ以降の挙動に胚ごとの差異が見られた。栄養外胚葉細胞のアポトーシスにともなって，内部細胞塊のOct3/4陽性細胞も一部はアポトーシスを起こし，たとえ少数でも生き残こればそこからES様細胞の成長が見られた。一方，Oct3/4陽性細胞すべてが消失したものや，Oct3/4陰性細胞からは樹立できなかった。カスパーゼ阻害剤であるZ-VAD-FMKを培地中に加えると，Oct3/4陽性細胞の減少が抑えられ，結果的に樹立成績が上がった。また，樹立成績を大きく上昇させることで知られている分化抑制剤である3iを培地に加えると，Oct3/4陽性細胞のアポトーシスが起きず，ES様細胞樹立の速度や成功率が向上した。

DOI： 10.14882/jrds.105.0_116

J-GLOBAL

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記述言語：日本語   掲載種別：機関テクニカルレポート，技術報告書，プレプリント等  

添付ファイル： CST_Application_71.pdf

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

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記述言語：日本語  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：口頭発表（招待・特別）  

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記述言語：日本語   会議種別：口頭発表（招待・特別）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：口頭発表（招待・特別）  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：ポスター発表  

開催地：Oberstdorf, Germany  

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記述言語：英語   会議種別：口頭発表（一般）  

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種別：出前授業

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種別：出前授業

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種別：出前授業

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種別：新聞・雑誌

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