27 results on '"Kiyonari, Hiroshi"'
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2. Forkhead transcription factor FoxO1 in adipose tissue regulates energy storage and expenditure
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Nakae, Jun, Cao, Yongheng, Oki, Miyo, Orba, Yasuko, Sawa, Hirofumi, Kiyonari, Hiroshi, Iskandar, Kristy, Suga, Koji, Lombes, Marc, and Hayashi, Yoshitake
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Gene expression -- Health aspects ,Adipose tissues -- Health aspects ,Glucose metabolism -- Health aspects ,Health ,Health aspects - Abstract
OBJECTIVE--Adipose tissue serves as an integrator of various physiological pathways, energy balance, and glucose homeostasis. Forkhead box-containing protein 0 subfamily (FoxO) 1 mediates insulin action at the transcriptional level. However, [...]
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- 2008
3. Tracing the origin of hair follicle stem cells
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Morita, Ritsuko, Sanzen, Noriko, Sasaki, Hiroko, Hayashi, Tetsutaro, Umeda, Mana, Yoshimura, Mika, Yamamoto, Takaki, Shibata, Tatsuo, Abe, Takaya, Kiyonari, Hiroshi, Furuta, Yasuhide, Nikaido, Itoshi, and Fujiwara, Hironobu
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Tissue stem cells are generated from a population of embryonic progenitors through organ-specific morphogenetic events1,2. Although tissue stem cells are central to organ homeostasis and regeneration, it remains unclear how they are induced during development, mainly because of the lack of markers that exclusively label prospective stem cells. Here we combine marker-independent long-term 3D live imaging and single-cell transcriptomics to capture a dynamic lineage progression and transcriptome changes in the entire epithelium of the mouse hair follicle as it develops. We found that the precursors of different epithelial lineages were aligned in a 2D concentric manner in the basal layer of the hair placode. Each concentric ring acquired unique transcriptomes and extended to form longitudinally aligned, 3D cylindrical compartments. Prospective bulge stem cells were derived from the peripheral ring of the placode basal layer, but not from suprabasal cells (as was previously suggested3). The fate of placode cells is determined by the cell position, rather than by the orientation of cell division. We also identified 13 gene clusters: the ensemble expression dynamics of these clusters drew the entire transcriptional landscape of epithelial lineage diversification, consistent with cell lineage data. Combining these findings with previous work on the development of appendages in insects4,5, we describe the ‘telescope model’, a generalized model for the development of ectodermal organs in which 2D concentric zones in the placode telescope out to form 3D longitudinally aligned cylindrical compartments.
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- 2021
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4. LUBAC accelerates B-cell lymphomagenesis by conferring resistance to genotoxic stress on B cells
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Jo, Tomoyasu, Nishikori, Momoko, Kogure, Yasunori, Arima, Hiroshi, Sasaki, Katsuhiro, Sasaki, Yoshiteru, Nakagawa, Tomoko, Iwai, Fumie, Momose, Shuji, Shiraishi, Aki, Kiyonari, Hiroshi, Kagaya, Noritaka, Onuki, Tetsuo, Shin-ya, Kazuo, Yoshida, Minoru, Kataoka, Keisuke, Ogawa, Seishi, Iwai, Kazuhiro, and Takaori-Kondo, Akifumi
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The linear ubiquitin chain assembly complex (LUBAC) is a key regulator of NF-κB signaling. Activating single-nucleotide polymorphisms of HOIP, the catalytic subunit of LUBAC, are enriched in patients with activated B-cell–like (ABC) diffuse large B-cell lymphoma (DLBCL), and expression of HOIP, which parallels LUBAC activity, is elevated in ABC-DLBCL samples. Thus, to clarify the precise roles of LUBAC in lymphomagenesis, we generated a mouse model with augmented expression of HOIP in B cells. Interestingly, augmented HOIP expression facilitated DLBCL-like B-cell lymphomagenesis driven by MYD88-activating mutation. The developed lymphoma cells partly shared somatic gene mutations with human DLBCLs, with increased frequency of a typical AID mutation pattern. In vitro analysis revealed that HOIP overexpression protected B cells from DNA damage-induced cell death through NF-κB activation, and analysis of the human DLBCL database showed that expression of HOIP positively correlated with gene signatures representing regulation of apoptosis signaling, as well as NF-κB signaling. These results indicate that HOIP facilitates lymphomagenesis by preventing cell death and augmenting NF-κB signaling, leading to accumulation of AID-mediated mutations. Furthermore, a natural compound that specifically inhibits LUBAC was shown to suppress the tumor growth in a mouse transplantation model. Collectively, our data indicate that LUBAC is crucially involved in B-cell lymphomagenesis through protection against DNA damage–induced cell death and is a suitable therapeutic target for B-cell lymphomas.
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- 2020
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5. Asrij/OCIAD1 suppresses CSN5-mediated p53 degradation and maintains mouse hematopoietic stem cell quiescence
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Sinha, Saloni, Dwivedi, Tirath Raj, Yengkhom, Roja, Bheemsetty, Venkata Anudeep, Abe, Takaya, Kiyonari, Hiroshi, VijayRaghavan, K., and Inamdar, Maneesha S.
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Inactivation of the tumor suppressor p53 is essential for unrestrained growth of cancers. However, only 11% of hematological malignancies have mutant p53. Mechanisms that cause wild-type p53 dysfunction and promote leukemia are inadequately deciphered. The stem cell protein Asrij/OCIAD1 is misexpressed in several human hematological malignancies and implicated in the p53 pathway and DNA damage response. However, Asrij function in vertebrate hematopoiesis remains unknown. We generated the first asrij null (knockout [KO]) mice and show that they are viable and fertile with no gross abnormalities. However, by 6 months, they exhibit increased peripheral blood cell counts, splenomegaly, and an expansion of bone marrow hematopoietic stem cells (HSCs) with higher myeloid output. HSCs lacking Asrij are less quiescent and more proliferative with higher repopulation potential as observed from serial transplantation studies. However, stressing KO mice with sublethal ? irradiation or multiple injections of 5-fluorouracil results in reduced survival and rapid depletion of hematopoietic stem/progenitor cells (HSPCs) by driving them into proliferative exhaustion. Molecular and biochemical analyses revealed increased polyubiquitinated protein levels, Akt/STAT5 activation and COP9 signalosome subunit 5 (CSN5)-mediated p53 ubiquitination, and degradation in KO HSPCs. Further, we show that Asrij sequesters CSN5 via its conserved OCIA domain, thereby preventing p53 degradation. In agreement, Nutlin-3 treatment of KO mice restored p53 levels and reduced high HSPC frequencies. Thus, we provide a new mouse model resembling myeloproliferative disease and identify a posttranslational regulator of wild-type p53 essential for maintaining HSC quiescence that could be a potential target for pharmacological intervention.
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- 2019
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6. Mouse embryonic stem cells embody organismal-level cold resistance
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Suita, Koukyou, Ishikawa, Kiyomi, Kaneko, Mari, Wataki, Ayaka, Takahashi, Masayo, Kiyonari, Hiroshi, and Sunagawa, Genshiro A.
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During hibernation, some mammals show low body temperatures (<10°C). Tissues from hibernators exhibit cold resistance even when the animal is not hibernating. Mice can also enter hypothermic fasting-induced torpor (FIT), but the cold resistance of FIT has never been related to their tissues. Here, we show that an inbred mouse STM2 exhibits lower body temperature during FIT than C57BL/6J or MYS/Mz. Thus, STM2 resists the cold more than other strains. Analysis of strain-specific mouse embryonic stem (ES) cells shows that STM2 ES cells are more cold-resistant than others and rely on the oxidative phosphorylation (OXPHOS) pathway but respire independently of the electron transfer chain complex I in the cold. We also found that the liver of STM2 uses OXPHOS more in cold than other strains. This study demonstrates that an organismal phenotype associated with torpor can be effectively studied in an in vitrosetup using mouse cells.
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- 2023
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7. Loss of SfpqCauses Long-Gene Transcriptopathy in the Brain
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Takeuchi, Akihide, Iida, Kei, Tsubota, Toshiaki, Hosokawa, Motoyasu, Denawa, Masatsugu, Brown, J.B., Ninomiya, Kensuke, Ito, Mikako, Kimura, Hiroshi, Abe, Takaya, Kiyonari, Hiroshi, Ohno, Kinji, and Hagiwara, Masatoshi
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Genes specifically expressed in neurons contain members with extended long introns. Longer genes present a problem with respect to fulfilment of gene length transcription, and evidence suggests that dysregulation of long genes is a mechanism underlying neurodegenerative and psychiatric disorders. Here, we report the discovery that RNA-binding protein Sfpq is a critical factor for maintaining transcriptional elongation of long genes. We demonstrate that Sfpq co-transcriptionally binds to long introns and is required for sustaining long-gene transcription by RNA polymerase II through mediating the interaction of cyclin-dependent kinase 9 with the elongation complex. Phenotypically, Sfpqdisruption caused neuronal apoptosis in developing mouse brains. Expression analysis of Sfpq-regulated genes revealed specific downregulation of developmentally essential neuronal genes longer than 100 kb in Sfpq-disrupted brains; those genes are enriched in associations with neurodegenerative and psychiatric diseases. The identified molecular machinery yields directions for targeted investigations of the association between long-gene transcriptopathy and neuronal diseases.
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- 2018
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8. The Inv compartment of renal cilia is an intraciliary signal-activating center to phosphorylate ANKS6
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Nakajima, Yoshiro, Kiyonari, Hiroshi, Mukumoto, Yoshiko, and Yokoyama, Takahiko
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Connections between cilia and renal cystic diseases are well known, yet molecular mechanisms remain undefined. Cysto-proteins localized in the Inv compartment of cilia (INV, NPHP3, NEK8, and ANKS6) constitute a distinct group. Here we created and analyzed mutant mice (G2A mice) with a defective cilia localization signal in the Nphp3gene. Mutant NPHP3 was absent the binding capacity of UNC119, a carrier protein responsible for the delivery of myristoylated cargo to the cilium, so ciliary localization was reduced or lost in the kidney but not in the embryonic node. Mutant mice developed renal cysts but not situsabnormalities. Although ciliary localization of INV, NEK8, and ANKS6 did not change in the kidneys of Nphp3mutant mice, ANKS6 phosphorylation was impaired. In general, ANKS6 levels decrease with age in the kidneys of wild-type mice. However, cystic kidneys in G2A and Invmice maintained high levels of a non-phosphorylated form of ANKS6. We found INV and NPHP3 cooperate and promote ANKS6 phosphorylation by NEK8 in renal cilia. Thus, there is a novel signaling path from cilia in which ANKS6 functions as a signal mediator and link between cilia and the cytoplasm to regulate kidney morphogenesis.
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- 2018
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9. A three-dimensional single-cell-resolution whole-brain atlas using CUBIC-X expansion microscopy and tissue clearing
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Murakami, Tatsuya, Mano, Tomoyuki, Saikawa, Shu, Horiguchi, Shuhei, Shigeta, Daichi, Baba, Kousuke, Sekiya, Hiroshi, Shimizu, Yoshihiro, Tanaka, Kenji, Kiyonari, Hiroshi, Iino, Masamitsu, Mochizuki, Hideki, Tainaka, Kazuki, and Ueda, Hiroki
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A three-dimensional single-cell-resolution mammalian brain atlas will accelerate systems-level identification and analysis of cellular circuits underlying various brain functions. However, its construction requires efficient subcellular-resolution imaging throughout the entire brain. To address this challenge, we developed a fluorescent-protein-compatible, whole-organ clearing and homogeneous expansion protocol based on an aqueous chemical solution (CUBIC-X). The expanded, well-cleared brain enabled us to construct a point-based mouse brain atlas with single-cell annotation (CUBIC-Atlas). CUBIC-Atlas reflects inhomogeneous whole-brain development, revealing a significant decrease in the cerebral visual and somatosensory cortical areas during postnatal development. Probabilistic activity mapping of pharmacologically stimulated Arc-dVenus reporter mouse brains onto CUBIC-Atlas revealed the existence of distinct functional structures in the hippocampal dentate gyrus. CUBIC-Atlas is shareable by an open-source web-based viewer, providing a new platform for whole-brain cell profiling. The authors developed a CUBIC tissue clearing and expansion method to generate an editable, point-based single-cell-resolution brain atlas. This atlas, termed CUBIC-Atlas, can be used for unbiased systems-level cellular analysis in whole mouse brain.
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- 2018
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10. Production of knock-in mice in a single generation from embryonic stem cells
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Ukai, Hideki, Kiyonari, Hiroshi, and Ueda, Hiroki R
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The system-level identification and analysis of molecular networks in mammals can be accelerated by 'next-generation' genetics, defined as genetics that does not require crossing of multiple generations of animals in order to achieve the desired genetic makeup. We have established a highly efficient procedure for producing knock-in (KI) mice within a single generation, by optimizing the genome-editing protocol for KI embryonic stem (ES) cells and the protocol for the generation of fully ES-cell-derived mice (ES mice). Using this protocol, the production of chimeric mice is eliminated, and, therefore, there is no requirement for the crossing of chimeric mice to produce mice that carry the KI gene in all cells of the body. Our procedure thus shortens the time required to produce KI ES mice from about a year to ∼3 months. Various kinds of KI ES mice can be produced with a minimized amount of work, facilitating the elucidation of organism-level phenomena using a systems biology approach. In this report, we describe the basic technologies and protocols for this procedure, and discuss the current challenges for next-generation mammalian genetics in organism-level systems biology studies.
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- 2017
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11. Essential role of CCL21 in establishment of central self-tolerance in T cells
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Kozai, Mina, Kubo, Yuki, Katakai, Tomoya, Kondo, Hiroyuki, Kiyonari, Hiroshi, Schaeuble, Karin, Luther, Sanjiv A., Ishimaru, Naozumi, Ohigashi, Izumi, and Takahama, Yousuke
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The chemokine receptor CCR7 directs T cell relocation into and within lymphoid organs, including the migration of developing thymocytes into the thymic medulla. However, how three functional CCR7 ligands in mouse, CCL19, CCL21Ser, and CCL21Leu, divide their roles in immune organs is unclear. By producing mice specifically deficient in CCL21Ser, we show that CCL21Ser is essential for the accumulation of positively selected thymocytes in the thymic medulla. CCL21Ser-deficient mice were impaired in the medullary deletion of self-reactive thymocytes and developed autoimmune dacryoadenitis. T cell accumulation in the lymph nodes was also defective. These results indicate a nonredundant role of CCL21Ser in the establishment of self-tolerance in T cells in the thymic medulla, and reveal a functional inequality among CCR7 ligands in vivo.
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- 2017
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12. Hepatic phosphatidylcholine catabolism driven by PNPLA7 and PNPLA8 supplies endogenous choline to replenish the methionine cycle with methyl groups
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Hirabayashi, Tetsuya, Kawaguchi, Mai, Harada, Sayaka, Mouri, Misa, Takamiya, Rina, Miki, Yoshimi, Sato, Hiroyasu, Taketomi, Yoshitaka, Yokoyama, Kohei, Kobayashi, Tetsuyuki, Tokuoka, Suzumi M., Kita, Yoshihiro, Yoda, Emiko, Hara, Shuntaro, Mikami, Kyohei, Nishito, Yasumasa, Kikuchi, Norihito, Nakata, Rieko, Kaneko, Mari, Kiyonari, Hiroshi, Kasahara, Kohji, Aiba, Toshiki, Ikeda, Kazutaka, Soga, Tomoyoshi, Kurano, Makoto, Yatomi, Yutaka, and Murakami, Makoto
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Choline supplies methyl groups for regeneration of methionine and the methyl donor S-adenosylmethionine in the liver. Here, we report that the catabolism of membrane phosphatidylcholine (PC) into water-soluble glycerophosphocholine (GPC) by the phospholipase/lysophospholipase PNPLA8-PNPLA7 axis enables endogenous choline stored in hepatic PC to be utilized in methyl metabolism. PNPLA7-deficient mice show marked decreases in hepatic GPC, choline, and several metabolites related to the methionine cycle, accompanied by various signs of methionine insufficiency, including growth retardation, hypoglycemia, hypolipidemia, increased energy consumption, reduced adiposity, increased fibroblast growth factor 21 (FGF21), and an altered histone/DNA methylation landscape. Moreover, PNPLA8-deficient mice recapitulate most of these phenotypes. In contrast to wild-type mice fed a methionine/choline-deficient diet, both knockout strains display decreased hepatic triglyceride, likely via reductions of lipogenesis and GPC-derived glycerol flux. Collectively, our findings highlight the biological importance of phospholipid catabolism driven by PNPLA8/PNPLA7 in methyl group flux and triglyceride synthesis in the liver.
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- 2023
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13. Quantitative Dynamics of Chromatin Remodeling during Germ Cell Specification from Mouse Embryonic Stem Cells
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Kurimoto, Kazuki, Yabuta, Yukihiro, Hayashi, Katsuhiko, Ohta, Hiroshi, Kiyonari, Hiroshi, Mitani, Tadahiro, Moritoki, Yoshinobu, Kohri, Kenjiro, Kimura, Hiroshi, Yamamoto, Takuya, Katou, Yuki, Shirahige, Katsuhiko, and Saitou, Mitinori
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Germ cell specification is accompanied by epigenetic remodeling, the scale and specificity of which are unclear. Here, we quantitatively delineate chromatin dynamics during induction of mouse embryonic stem cells (ESCs) to epiblast-like cells (EpiLCs) and from there into primordial germ cell-like cells (PGCLCs), revealing large-scale reorganization of chromatin signatures including H3K27me3 and H3K9me2 patterns. EpiLCs contain abundant bivalent gene promoters characterized by low H3K27me3, indicating a state primed for differentiation. PGCLCs initially lose H3K4me3 from many bivalent genes but subsequently regain this mark with concomitant upregulation of H3K27me3, particularly at developmental regulatory genes. PGCLCs progressively lose H3K9me2, including at lamina-associated perinuclear heterochromatin, resulting in changes in nuclear architecture. T recruits H3K27ac to activate BLIMP1 and early mesodermal programs during PGCLC specification, which is followed by BLIMP1-mediated repression of a broad range of targets, possibly through recruitment and spreading of H3K27me3. These findings provide a foundation for reconstructing regulatory networks of the germline epigenome.
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- 2015
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14. Loss of a Rho-Regulated Actin Nucleator, mDia2, Impairs Cytokinesis during Mouse Fetal Erythropoiesis
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Watanabe, Sadanori, De Zan, Tihana, Ishizaki, Toshimasa, Yasuda, Shingo, Kamijo, Hiroshi, Yamada, Daisuke, Aoki, Tomohiro, Kiyonari, Hiroshi, Kaneko, Hiroshi, Shimizu, Ritsuko, Yamamoto, Masayuki, Goshima, Gohta, and Narumiya, Shuh
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The small GTPase Rho and mDia2, a Rho-regulated actin nucleator, function as critical regulators of cytokinesis in cultured cells. However, their involvement in cytokinesis during mammalian development remains unknown. Here, we generated mice deficient in mDia2 and examined the role of Rho signaling in cytokinesis during development. mDia2-deficient mice survive until embryonic day 11.5 (E11.5), exhibit severe anemia with multinucleate erythroblasts, and die in utero by E12.5. mDia2-deficient erythroid cells differentiate normally, though in a delayed manner, but exhibit cytokinesis failure with decreased accumulation of F-actin in the cleavage furrow during late differentiation from proerythroblasts. On the other hand, inactivation of Rho induces cytokinesis failure from the earlier progenitor stage. mDia2-deficient erythroblasts, however, are able to enucleate their nuclei. Our findings have thus revealed that mDia2 functions critically in cytokinesis in vivo during erythropoiesis and further suggest that the cytokinesis mechanism in development diverges downstream of Rho. They also demonstrate that cytokinesis and enucleation utilize different mechanisms.
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- 2013
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15. Molecular Identification of tw5: Vps52Promotes Pluripotential Cell Differentiation through Cell–Cell Interactions
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Sugimoto, Michihiko, Kondo, Masayo, Hirose, Michiko, Suzuki, Misao, Mekada, Kazuyuki, Abe, Takaya, Kiyonari, Hiroshi, Ogura, Atsuo, Takagi, Nobuo, Artzt, Karen, and Abe, Kuniya
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After implantation, pluripotent epiblasts are converted to embryonic ectoderm through cell–cell interactions that significantly change the transcriptional and epigenetic networks. An entrée to understanding this vital developmental transition is the tw5mutation of the mouse tcomplex. This mutation produces highly specific defects in the embryonic ectoderm before gastrulation, leading to death of the embryonic ectoderm. Using a positional cloning approach, we have now identified the mutated gene, completing a decades-long search. The gene, vacuolar protein sorting 52(Vps52), is a mouse homolog of yeast VPS52that is involved in the retrograde trafficking of endosomes. Our data suggest that Vps52acts in extraembryonic tissues to support the growth and differentiation of embryonic ectoderm via cell–cell interactions. It is also required in the formation of embryonic structures at a later stage of development, revealing hitherto unknown functions of Vps52in the development of a multicellular organism.
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- 2012
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16. Lineage tracing analysis defines erythropoietin-producing cells as a distinct subpopulation of resident fibroblasts with unique behaviors
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Kaneko, Keiichi, Sato, Yuki, Uchino, Eiichiro, Toriu, Naoya, Shigeta, Mayo, Kiyonari, Hiroshi, Endo, Shuichiro, Fukuma, Shingo, and Yanagita, Motoko
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Erythropoietin (Epo) is produced by a subpopulation of resident fibroblasts in the healthy kidney. We have previously demonstrated that, during kidney fibrosis, kidney fibroblasts including Epo-producing cells transdifferentiate into myofibroblasts and lose their Epo-producing ability. However, it remains unclear whether Epo-producing cells survive and transform into myofibroblasts during fibrosis because previous studies did not specifically label Epo-producing cells in pathophysiological conditions. Here, we generated EpoCreERT2/+mice, a novel mouse strain that enables labeling of Epo-producing cells at desired time points and examined the behaviors of Epo-producing cells under pathophysiological conditions. Lineage-labeled cells that were producing Epo when labeled were found to be a small subpopulation of fibroblasts located in the interstitium of the kidney, and their number increased during phlebotomy-induced anemia. Around half of lineage-labeled cells expressed Epo mRNA, and this percentage was maintained even 16 weeks after recombination, supporting the idea that a distinct subpopulation of cells with Epo-producing ability makes Epo repeatedly. During fibrosis caused by ureteral obstruction, EpoCreERT2/+-labeled cells were found to transdifferentiate into myofibroblasts with concomitant loss of Epo-producing ability, and their numbers and the proportion among resident fibroblasts increased during fibrosis, indicating their high proliferative capacity. Finally, we confirmed that EpoCreERT2/+-labeled cells that lost their Epo-producing ability during fibrosis regained their ability after kidney repair due to relief of the ureteral obstruction. Thus, our analyses have revealed previously unappreciated characteristic behaviors of Epo-producing cells, which had not been clearly distinguished from those of resident fibroblasts.
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- 2022
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17. Loss of Hrs in the Central Nervous System Causes Accumulation of Ubiquitinated Proteins and Neurodegeneration
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Tamai, Keiichi, Toyoshima, Masafumi, Tanaka, Nobuyuki, Yamamoto, Noriko, Owada, Yuji, Kiyonari, Hiroshi, Murata, Kazuko, Ueno, Yoshiyuki, Ono, Masao, Shimosegawa, Tooru, Yaegashi, Nobuo, Watanabe, Masahiko, and Sugamura, Kazuo
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The endosomal sorting complex required for transport (ESCRT) proteins form multimolecular complexes that control multivesicular body formation, endosomal sorting, and transport ubiquitinated membrane proteins (including cell-surface receptors) to the endosomes for degradation. There is accumulating evidence that endosomal dysfunction is linked to neural cell degeneration in vitro, but little is known about the relationship between neural disorders and ESCRT proteins in vivo. Here we specifically deleted the hrsgene, ESCRT-0, in the neurons of mice by crossing loxP-flanked hrsmice with transgenic mice expressing the synapsin-I Cre protein (SynI-cre). Histological analyses revealed that both apoptosis and a loss of hippocampal CA3 pyramidal neurons occurred in the hrsflox/flox;SynI-cremice. Notably, the hrsflox/flox;SynI-cremice accumulated ubiquitinated proteins, such as glutamate receptors and an autophagy-regulating protein, p62. These molecules are particularly prominent in the hippocampal CA3 neurons and cerebral cortex with advancing age. Accordingly, we found that both locomotor activity and learning ability were severely reduced in the hrsflox/flox;SynI-cremice. These data suggest that Hrs plays an important role in neural cell survival in vivoand provide an animal model for neurodegenerative diseases that are known to be commonly affected by the generation of proteinaceous aggregates.
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- 2008
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18. A new serine/threonine protein kinase, Omphk1, essential to ventral body wall formation
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Hirano, Mariko, Kiyonari, Hiroshi, Inoue, Ai, Furushima, Kenryo, Murata, Takuya, Suda, Yoko, and Aizawa, Shinichi
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Here, we report a new serine/threonine protein kinase of the SNF1 subfamily Omphk1. Two Omphk homologues exist in each vertebrate species, and one homologue exists in Drosophila and Caenorhabditis elegans; the kinase domain is highly conserved among these homologues, and several domains are conserved among vertebrate Omphk. Omphk1 expression dynamically changes in the developing central nervous system, is found ubiquitously in epidermis, and is present uniquely in several other tissues. Its expression is also found in each tissue associated with the ventral body wall closure: the primary body wall composed of primitive ectoderm and each component of the secondary body wall. Concomitantly, its null mutant exhibits omphalocele with a failure in closure of the secondary body wall. There are no apparent gross morphological defects in brain, however, despite the unique Omphk1 expression in this tissue. Developmental Dynamics 235:2229–2237, 2006. © 2006 Wiley‐Liss, Inc.
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- 2006
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19. Characterization of Opr deficiency in mouse brain: Subtle defects in dorsomedial telencephalon and medioventral forebrain
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Furushima, Kenryo, Murata, Takuya, Kiyonari, Hiroshi, and Aizawa, Shinichi
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Opr/Zic5 is a zinc‐finger gene belonging to, and unique in, the opa/Zic family. Its expression is found in the anterior epiblast and anterior neuroectoderm during gastrulation and early neurulation. Later, we found the expression characteristic in the dorsomedial parts of forebrain and midbrain. However, no defects were apparent in embryonic day 10.5 Opr null mutants, and subtle defects were later found in medial pallium and ventral structures of forebrain, suggesting the compensation of Opr deficiency by its cognate(s). Developmental Dynamics 232:1056–1061, 2005. © 2005 Wiley‐Liss, Inc.
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- 2005
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20. Dysfunction of the proteoglycan Tsukushi causes hydrocephalus through altered neurogenesis in the subventricular zone in mice
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Ito, Naofumi, Riyadh, M. Asrafuzzaman, Ahmad, Shah Adil Ishtiyaq, Hattori, Satoko, Kanemura, Yonehiro, Kiyonari, Hiroshi, Abe, Takaya, Furuta, Yasuhide, Shinmyo, Yohei, Kaneko, Naoko, Hirota, Yuki, Lupo, Giuseppe, Hatakeyama, Jun, Abdulhaleem M, Felemban Athary, Anam, Mohammad Badrul, Yamaguchi, Masahiro, Takeo, Toru, Takebayashi, Hirohide, Takebayashi, Minoru, Oike, Yuichi, Nakagata, Naomi, Shimamura, Kenji, Holtzman, Michael J., Takahashi, Yoshiko, Guillemot, Francois, Miyakawa, Tsuyoshi, Sawamoto, Kazunobu, and Ohta, Kunimasa
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Tsukushi loss in the mouse subventricular zone led to altered neurogenesis and hydrocephalus.
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- 2021
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21. NeuroGT: A brain atlas of neurogenic tagging CreER drivers for birthdate-based classification and manipulation of mouse neurons
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Hirata, Tatsumi, Tohsato, Yukako, Itoga, Hiroya, Shioi, Go, Kiyonari, Hiroshi, Oka, Sanae, Fujimori, Toshihiko, and Onami, Shuichi
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Neuronal birthdate is one of the major determinants of neuronal phenotypes. However, most birthdating methods are retrospective in nature, allowing very little experimental access to the classified neuronal subsets. Here, we introduce four neurogenic tagging mouse lines, which can assign CreER-loxPrecombination to neuron subsets that share the same differentiation timing in living animals and enable various experimental manipulations of the classified subsets. We constructed a brain atlas of the neurogenic tagging mouse lines (NeuroGT), which includes holistic image data of the loxP-recombined neurons and their processes across the entire brain that were tagged on each single day during the neurodevelopmental period. This image database, which is open to the public, offers investigators the opportunity to find specific neurogenic tagging driver lines and the stages of tagging appropriate for their own research purposes.
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- 2021
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22. Pronuclear Microinjection during S-Phase Increases the Efficiency of CRISPR-Cas9-Assisted Knockin of Large DNA Donors in Mouse Zygotes
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Abe, Takaya, Inoue, Ken-ichi, Furuta, Yasuhide, and Kiyonari, Hiroshi
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In CRISPR-Cas9-assisted knockin (KI) in zygotes, a remaining challenge is routinely achieving high-efficiency KI of large (kilobase-sized) DNA elements. Here, we focus on the timing of pronuclear injection and establish a reliable homologous recombination (HR)-based method to generate large KIs in zygotes compared with two other types of KI strategies involving distinct DNA repair pathways. At the ROSA26locus, pronuclear injection with CRISPR RNA (crRNA), trans-activating crRNA (tracrRNA), and Cas9 protein at the S phase by using the HR-based method yields the most efficient and accurate KIs (up to 70%). This approach is also generally effective for generating large KI alleles at other gene loci. We further apply our method to efficiently obtain biallelic ROSA26KIs by sequential injection into both pronuclei. Our results suggest that delivery of genome editing components and donor DNA into S-phase zygotes is critical for efficient KI of large DNA elements.
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- 2020
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23. Changes in Wnt-Dependent Neuronal Morphology Underlie the Anatomical Diversification of Neocortical Homologs in Amniotes
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Nomura, Tadashi, Ohtaka-Maruyama, Chiaki, Kiyonari, Hiroshi, Gotoh, Hitoshi, and Ono, Katsuhiko
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The six-layered neocortex is a shared characteristic of all mammals, but not of non-mammalian species, and its formation requires an inside-out pattern of neuronal migration. The extant reptilian dorsal cortex is thought to represent an ancestral form of the neocortex, although how the reptilian three-layered cortex is formed is poorly understood. Here, we show unique patterns of lamination and neuronal migration in the developing reptilian cortex. While the multipolar-to-bipolar transition of migrating neurons is essential for mammalian cortical development, the reptilian cortex lacks bipolar-shaped migrating neurons, resulting in an outside-in pattern of cortical development. Furthermore, dynamic regulation of Wnt signal strengths contributes to neuronal morphological changes, which is conserved across species. Our data preclude the idea that the six-layered mammalian neocortex emerged by simple addition to the reptilian dorsal cortex but suggest that the acquisition of a novel neuronal morphology based on conserved developmental programs contributed to neocortical evolution.
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- 2020
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24. Abstract 10375: Serum-induced Expression of Brain Natriuretic Peptide Contributes to Its Increase in Patients With Heart Failure
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Okamoto, Ryuji, Hashizume, Ryotaro, Suzuki, Noboru, Kiyonari, Hiroshi, and Ito, Masaaki
- Abstract
Introduction:It has been thought brain natriuretic peptide (BNP) is induced by undetermined stretch-activated receptors, however, which receptors are associated remains unknown. The stretch-activated receptors include mechanically gated channels, which can be activated by a mechanical stimulus alone, and mechanically modulated channels, which require nonmechanical stimuli such as agonists. Thus it is possible that serum-induced expression of BNP may contribute to the increase of BNP in patients with heart failure.Purpose:Our purpose is to examine whether serum-induced BNP expression (iBNP) partly contributes to the increase in BNP in patients with heart failure or not.Methods:We generated the BNP reporter mice by knocking luciferase cDNA in the initiation site of NPPB. Left anterior descending (LAD) coronary artery was ligated to study myocardial infarction. In vivo imaging of luciferase was performed in the BNP reporter mice after the intraperitoneal injection of luciferin. Neonatal cardiomyocytes were isolated and cultured from 2-day-old neonates. These cardiomyocytes were stimulated for 24 hours with 20% serum from patients with heart failure or control hypertensive patients without heart failure and the luciferase activity was measured (n=50 in each group).Results:The in vivo imaging system showed the activity of BNP was high in 1day-old neonates and the reactivation of BNP in the adult heart after LAD ligation could be monitored by the luciferase activity. The luciferase activity was significantly higher in cultured neonatal cardiomyocytes 24h after the treatment of serum from patients with heart failure than control patients without heart failure.Conclusions:These results indicate the elevation of BNP in patients of heart failure partly due to the iBNP from heart.
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- 2019
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25. Metalloprotease-Dependent Attenuation of BMP Signaling Restricts Cardiac Neural Crest Cell Fate
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Arai, Hiroyuki N., Sato, Fuminori, Yamamoto, Takuya, Woltjen, Knut, Kiyonari, Hiroshi, Yoshimoto, Yuki, Shukunami, Chisa, Akiyama, Haruhiko, Kist, Ralf, and Sehara-Fujisawa, Atsuko
- Abstract
In higher vertebrates, cephalic neural crest cells (NCCs) form craniofacial skeleton by differentiating into chondrocytes and osteoblasts. A subpopulation of cephalic NCCs, cardiac NCCs (CNCCs), migrates to the heart. However, CNCCs mostly do not yield skeletogenic derivatives, and the molecular mechanisms of this fate restriction remain elusive. We identify a disintegrin and metalloprotease 19 (Adam19) as a position-specific fate regulator of NCCs. Adam19-depleted mice abnormally form NCC-derived cartilage in their hearts through the upregulation of Sox9 levels in CNCCs. Moreover, NCC-lineage-specific Sox9-overexpressing mice recapitulate CNCC chondrogenesis. In vitroexperiments show that Adam19 mediates the cleavage of bone morphogenic protein (BMP) type I receptor Alk2 (Acvr1), whereas pharmacogenetic approaches reveal that Adam19 inhibits CNCC chondrogenesis by suppressing the BMP-Sox9 cascade, presumably through processing Alk2. These findings suggest a metalloprotease-dependent mechanism attenuating cellular responsiveness to BMP ligands, which is essential for both the positional restriction of NCC skeletogenesis and normal heart development.
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- 2019
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26. Muscarinic Acetylcholine Receptors Chrm1and Chrm3Are Essential for REM Sleep
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Niwa, Yasutaka, Kanda, Genki N., Yamada, Rikuhiro G., Shi, Shoi, Sunagawa, Genshiro A., Ukai-Tadenuma, Maki, Fujishima, Hiroshi, Matsumoto, Naomi, Masumoto, Koh-hei, Nagano, Mamoru, Kasukawa, Takeya, Galloway, James, Perrin, Dimitri, Shigeyoshi, Yasufumi, Ukai, Hideki, Kiyonari, Hiroshi, Sumiyama, Kenta, and Ueda, Hiroki R.
- Abstract
Sleep regulation involves interdependent signaling among specialized neurons in distributed brain regions. Although acetylcholine promotes wakefulness and rapid eye movement (REM) sleep, it is unclear whether the cholinergic pathway is essential (i.e., absolutely required) for REM sleep because of redundancy from neural circuits to molecules. First, we demonstrate that synaptic inhibition of TrkA+ cholinergic neurons causes a severe short-sleep phenotype and that sleep reduction is mostly attributable to a shortened sleep duration in the dark phase. Subsequent comprehensive knockout of acetylcholine receptor genes by the triple-target CRISPR method reveals that a similar short-sleep phenotype appears in the knockout of two Gq-type acetylcholine receptors Chrm1and Chrm3. Strikingly, Chrm1and Chrm3double knockout chronically diminishes REM sleep to an almost undetectable level. These results suggest that muscarinic acetylcholine receptors, Chrm1and Chrm3,are essential for REM sleep.
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- 2018
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27. Angiopoietin-1 Guides Directional Angiogenesis Through Integrin αvβ5Signaling for Recovery of Ischemic Retinopathy
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Lee, Junyeop, Kim, Kyung Eun, Choi, Dong-Kyu, Jang, Jeon Yeob, Jung, Ji-Jung, Kiyonari, Hiroshi, Shioi, Go, Chang, Woohyok, Suda, Toshio, Mochizuki, Naoki, Nakaoka, Yoshikazu, Komuro, Issei, Yoo, Ook-Joon, and Koh, Gou Young
- Abstract
Angiopoietin-1 supplementation stimulates guided angiogenesis and promotes the formation of a healthy vascular network in a mouse model of ischemic retinopathy.
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- 2013
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