研究者詳細 - 岡野　栄之

論文 - 岡野　栄之

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Investigation of brain science and neurological/psychiatric disorders using genetically modified non-human primates

Okano H., Kishi N.

Current Opinion in Neurobiology （Current Opinion in Neurobiology） 50 1 - 6 2018年06月

ISSN 09594388

© 2017 Elsevier Ltd Although mice have been the most frequently used experimental animals in many research fields due to well-established gene manipulation techniques, recent evidence has revealed that rodent models do not always recapitulate pathophysiology of human neurological and psychiatric diseases due to the differences between humans and rodents. The recent developments in gene manipulation of non-human primate have been attracting much attention in the biomedical research field, because non-human primates have more applicable brain structure and function than rodents. In this review, we summarize recent progress on genetically-modified non-human primates including transgenic and knockout animals using genome editing technology.

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Nestin expression is differently regulated between odontoblasts and the subodontoblastic layer in mice

Nakatomi M., Quispe-Salcedo A., Sakaguchi M., Ida-Yonemochi H., Okano H., Ohshima H.

Histochemistry and Cell Biology （Histochemistry and Cell Biology） 149 （ 4 ） 383 - 391 2018年04月

ISSN 09486143

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. The Nestin gene encodes type VI intermediate filament and is known to be expressed in undifferentiated cells during neurogenesis and myogenesis. To regulate Nestin expression, the first or second intron enhancer is activated in a tissue-dependent manner, for example, the former in mesodermal cells and the latter in neural stem cells. Although Nestin has also been used as a differentiation marker for odontoblasts during tooth development, how Nestin expression is regulated in odontoblasts remains unclear. Therefore, this study aimed to compare the expression patterns of Nestin-GFP (green fluorescent protein) with that of endogenous Nestin in developing teeth of Nestin-EGFP (enhanced GFP) transgenic mice, in which the second intron enhancer is connected with the EGFP domain, at postnatal 7d, 3w, and 8w. Immunohistochemical and in situ hybridization analyses revealed that endogenous Nestin protein and Nestin mRNA were intensely expressed in differentiated odontoblasts, while GFP immunoreactivity, which reflects the activity of Nestin second intron enhancer-mediated transcription, was mainly observed in the subodontoblastic layer. These results indicate that the first intron enhancer may be activated in differentiated odontoblasts. Intriguingly, Nestin-GFP expression in the subodontoblastic layer was found to be restricted to the coronal pulp of molars, which is susceptible to tooth injuries. Because the subodontoblastic layer serves as a reservoir of newly differentiated odontoblast-like cells upon exogenous stimuli to dentin, our findings suggest that the original odontoblasts and regenerated odontoblast-like cells may differently regulate Nestin expression.

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Generation of D1-1 TALEN isogenic control cell line from Dravet syndrome patient iPSCs using TALEN-mediated editing of the SCN1A gene

Tanaka Y., Sone T., Higurashi N., Sakuma T., Suzuki S., Ishikawa M., Yamamoto T., Mitsui J., Tsuji H., Okano H., Hirose S.

Stem Cell Research （Stem Cell Research） 28 100 - 104 2018年04月

ISSN 18735061

© 2018 Dravet syndrome (DS) is an infantile epileptic encephalopathy mainly caused by de novo mutations in the SCN1A gene encoding the α1 subunit of the voltage-gated sodium channel Nav1.1. As an in vitro model of this disease, we previously generated an induced pluripotent stem cell (iPSC) line from a patient with DS carrying a c.4933C>T (p.R1645*) substitution in SCN1A. Here, we describe developing a genome-edited control cell line from this DS iPSC line by substituting the point mutation with the wild-type residue. This artificial control iPSC line will be a powerful tool for research into the pathology of DS.

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Rostrocaudal areal patterning of human PSC-derived cortical neurons by FGF8 signaling

Imaizumi K., Fujimori K., Ishii S., Otomo A., Hosoi Y., Miyajima H., Warita H., Aoki M., Hadano S., Akamatsu W., Okano H.

eNeuro （eNeuro） 5 （ 2 ） 2018年03月

© 2018 Imaizumi et al. The cerebral cortex is subdivided into distinct areas that have particular functions. The rostrocaudal (R-C) gradient of fibroblast growth factor 8 (FGF8) signaling defines this areal identity during neural development. In this study, we recapitulated cortical R-C patterning in human pluripotent stem cell (PSC) cultures. Modulation of FGF8 signaling appropriately regulated the R-C markers, and the patterns of global gene expression resembled those of the corresponding areas of human fetal brains. Furthermore, we demonstrated the utility of this culture system in modeling the area-specific forebrain phenotypes [presumptive upper motor neuron (UMN) phenotypes] of amyotrophic lateral sclerosis (ALS). We anticipate that our culture system will contribute to studies of human neurodevelopment and neurological disease modeling.

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Digital gene atlas of neonate common marmoset brain

Shimogori T., Abe A., Go Y., Hashikawa T., Kishi N., Kikuchi S., Kita Y., Niimi K., Nishibe H., Okuno M., Saga K., Sakurai M., Sato M., Serizawa T., Suzuki S., Takahashi E., Tanaka M., Tatsumoto S., Toki M., U M., Wang Y., Windak K., Yamagishi H., Yamashita K., Yoda T., Yoshida A., Yoshida C., Yoshimoto T., Okano H.

Neuroscience Research （Neuroscience Research） 128 1 - 13 2018年03月

ISSN 01680102

© 2017 Elsevier Ireland Ltd and Japan Neuroscience Society Interest in the common marmoset (Callithrix jacchus) as a primate model animal has grown recently, in part due to the successful demonstration of transgenic marmosets. However, there is some debate as to the suitability of marmosets, compared to more widely used animal models, such as the macaque monkey and mouse. Especially, the usage of marmoset for animal models of human cognition and mental disorders, is still yet to be fully explored. To examine the prospects of the marmoset model for neuroscience research, the Marmoset Gene Atlas (https://gene-atlas.bminds.brain.riken.jp/) provides a whole brain gene expression atlas in the common marmoset. We employ in situ hybridization (ISH) to systematically analyze gene expression in neonate marmoset brains, which allows us to compare expression with other model animals such as mouse. We anticipate that these data will provide sufficient information to develop tools that enable us to reveal marmoset brain structure, function, cellular and molecular organization for primate brain research.

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Single-cell bioluminescence imaging of deep tissue in freely moving animals

Iwano S., Sugiyama M., Hama H., Watakabe A., Hasegawa N., Kuchimaru T., Tanaka K., Takahashi M., Ishida Y., Hata J., Shimozono S., Namiki K., Fukano T., Kiyama M., Okano H., Kizaka-Kondoh S., McHugh T., Yamamori T., Hioki H., Maki S., Miyawaki A.

Science （Science） 359 （ 6378 ） 935 - 939 2018年02月

ISSN 00368075

© 2017 The Authors. Bioluminescence is a natural light source based on luciferase catalysis of its substrate luciferin. We performed directed evolution on firefly luciferase using a red-shifted and highly deliverable luciferin analog to establish AkaBLI, an all-engineered bioluminescence in vivo imaging system. AkaBLI produced emissions in vivo that were brighter by a factor of 100 to 1000 than conventional systems, allowing noninvasive visualization of single cells deep inside freely moving animals. Single tumorigenic cells trapped in the mouse lung vasculature could be visualized. In the mouse brain, genetic labeling with neural activity sensors allowed tracking of small clusters of hippocampal neurons activated by novel environments. In a marmoset, we recorded video-rate bioluminescence from neurons in the striatum, a deep brain area, for more than 1 year. AkaBLI is therefore a bioengineered light source to spur unprecedented scientific, medical, and industrial applications.

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Down-regulation of ghrelin receptors on dopaminergic neurons in the substantia nigra contributes to Parkinson's disease-like motor dysfunction

Suda Y., Kuzumaki N., Sone T., Narita M., Tanaka K., Hamada Y., Iwasawa C., Shibasaki M., Maekawa A., Matsuo M., Akamatsu W., Hattori N., Okano H., Narita M.

Molecular Brain （Molecular Brain） 11 （ 1 ） 2018年02月

© 2018 The Author(s). Ghrelin exerts a wide range of physiological actions throughout the body and appears to be a promising target for disease therapy. Endogenous ghrelin receptors (GHSRs) are present in extrahypothalamic sites including the substantia nigra pars compacta (SNc), which is related to phenotypic dysregulation or frank degeneration in Parkinson's disease (PD). Here we found a dramatic decrease in the expression of GHSR in PD-specific induced pluripotent stem cell (iPSC)-derived dopaminergic (DAnergic) neurons generated from patients carrying parkin gene (PARK2) mutations compared to those from healthy controls. Consistently, a significant decrease in the expression of GHSR was found in DAnergic neurons of isogenic PARK2-iPSC lines that mimicked loss of function of the PARK2 gene through CRISPR Cas9 technology. Furthermore, either intracerebroventricular injection or microinjection into the SNc of the selective GHSR1a antagonist [D-Lys3]-GHRP6 in normal mice produced cataleptic behaviors related to dysfunction of motor coordination. These findings suggest that the down-regulation of GHSRs in SNc-DA neurons induced the initial dysfunction of DA neurons, leading to extrapyramidal disorder under PD.

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Data descriptor: The Brain/MINDS 3D digital marmoset brain atlas

Woodward A., Hashikawa T., Maeda M., Kaneko T., Hikishima K., Iriki A., Okano H., Yamaguchi Y.

Scientific Data （Scientific Data） 5 2018年02月

© Author(s) 2018. We present a new 3D digital brain atlas of the non-human primate, common marmoset monkey (Callithrix jacchus), with MRI and coregistered Nissl histology data. To the best of our knowledge this is the first comprehensive digital 3D brain atlas of the common marmoset having normalized multi-modal data, cortical and sub-cortical segmentation, and in a common file format (NIfTI). The atlas can be registered to new data, is useful for connectomics, functional studies, simulation and as a reference. The atlas was based on previously published work but we provide several critical improvements to make this release valuable for researchers. Nissl histology images were processed to remove illumination and shape artifacts and then normalized to the MRI data. Brain region segmentation is provided for both hemispheres. The data is in the NIfTI format making it easy to integrate into neuroscience pipelines, whereas the previous atlas was in an inaccessible file format. We also provide cortical, mid-cortical and white matter boundary segmentations useful for visualization and analysis.

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Elavl3 is essential for the maintenance of Purkinje neuron axons

Ogawa Y., Kakumoto K., Yoshida T., Kuwako K., Miyazaki T., Yamaguchi J., Konno A., Hata J., Uchiyama Y., Hirai H., Watanabe M., Darnell R., Okano H., Okano H.

Scientific reports （Scientific reports） 8 （ 1 ） 2018年02月

Neuronal Elav-like (nElavl or neuronal Hu) proteins are RNA-binding proteins that regulate RNA stability and alternative splicing, which are associated with axonal and synaptic structures. nElavl proteins promote the differentiation and maturation of neurons via their regulation of RNA. The functions of nElavl in mature neurons are not fully understood, although Elavl3 is highly expressed in the adult brain. Furthermore, possible associations between nElavl genes and several neurodegenerative diseases have been reported. We investigated the relationship between nElavl functions and neuronal degeneration using Elavl3-/- mice. Elavl3-/- mice exhibited slowly progressive motor deficits leading to severe cerebellar ataxia, and axons of Elavl3-/- Purkinje cells were swollen (spheroid formation), followed by the disruption of synaptic formation of axonal terminals. Deficit in axonal transport and abnormalities in neuronal polarity was observed in Elavl3-/- Purkinje cells. These results suggest that nElavl proteins are crucial for the maintenance of axonal homeostasis in mature neurons. Moreover, Elavl3-/- mice are unique animal models that constantly develop slowly progressive axonal degeneration. Therefore, studies of Elavl3-/- mice will provide new insight regarding axonal degenerative processes.

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Nitrative stress and tau accumulation in amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) in the Kii Peninsula, Japan

Hata Y., Ma N., Yoneda M., Morimoto S., Okano H., Murayama S., Kawanishi S., Kuzuhara S., Kokubo Y.

Frontiers in Neuroscience （Frontiers in Neuroscience） 11 （ JAN ） 2018年01月

ISSN 16624548

© 2018 Hata, Ma, Yoneda, Morimoto, Okano, Murayama, Kawanishi, Kuzuhara and Kokubo. Objective: The Kii Peninsula of Japan is known to be a high incidence area of amyotrophic lateral sclerosis/parkinsonism-dementia complex (Kii ALS/PDC) with tauopathy. Nitrative stress and oxidative stress on ALS/PDC and their relationship to tau pathology were clarified. Methods: Seven patients with Kii ALS/PDC (3 males and 4 females, average age 70.7 years, 3 with ALS, 2 with ALS with dementia, and 2 with PDC) were analyzed in this study. Five patients with Alzheimer's disease and five normal aged subjects were used as controls. Immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded temporal lobe sections (the hippocampal area including hippocampus, prosubiculum, subiculum, presubiculum, and parahippocampal gyri) using antibodies to detect phosphorylated tau (anti-AT-8), nitrated guanine (anti-8-NG), anti-iNOS, anti-NFκB, and oxidized guanine (anti-8-OHdG) antibodies. Results: Most hippocampal neurons of Kii ALS/PDC patients were stained with anti-8-NG, anti-iNOS, anti-NFκB, and anti-8-OHdG antibodies and some AT-8 positive neurons were co-stained with anti-8-NG antibody. The numbers of 8-NG positive neurons and 8-OHdG positive neurons were greater than AT-8 positive neurons and the number of 8-NG positive neurons was larger in patients with Kii ALS/PDC than in controls. Conclusion: Nitrative and oxidative stress may take priority over tau accumulation and lead to the neurodegeneration in Kii ALS/PDC.

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Chromatin remodeler CHD7 regulates the stem cell identity of human neural progenitors

Chai M., Sanosaka T., Okuno H., Zhou Z., Koya I., Banno S., Andoh-Noda T., Tabata Y., Shimamura R., Hayashi T., Ebisawa M., Sasagawa Y., Nikaido I., Okano H., Kohyama J.

Genes and Development （Genes and Development） 32 （ 2 ） 165 - 180 2018年01月

ISSN 08909369

© 2018 Chai et al. Multiple congenital disorders often present complex phenotypes, but how the mutation of individual genetic factors can lead to multiple defects remains poorly understood. In the present study, we used human neuroepithelial (NE) cells and CHARGE patient-derived cells as an in vitro model system to identify the function of chromodomain helicase DNA-binding 7 (CHD7) in NE–neural crest bifurcation, thus revealing an etiological link between the central nervous system (CNS) and craniofacial anomalies observed in CHARGE syndrome. We found that CHD7 is required for epigenetic activation of superenhancers and CNS-specific enhancers, which support the maintenance of the NE and CNS lineage identities. Furthermore, we found that BRN2 and SOX21 are downstream effectors of CHD7, which shapes cellular identities by enhancing a CNS-specific cellular program and indirectly repressing non-CNS-specific cellular programs. Based on our results, CHD7, through its interactions with superenhancer elements, acts as a regulatory hub in the orchestration of the spatiotemporal dynamics of transcription factors to regulate NE and CNS lineage identities.

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Activation of ventral tegmental area dopaminergic neurons reverses pathological allodynia resulting from nerve injury or bone cancer

Watanabe M., Narita M., Hamada Y., Yamashita A., Tamura H., Ikegami D., Kondo T., Shinzato T., Shimizu T., Fukuchi Y., Muto A., Okano H., Yamanaka A., Tawfik V., Kuzumaki N., Navratilova E., Porreca F., Narita M.

Molecular Pain （Molecular Pain） 14 2018年01月

© The Author(s) 2018. Chronic pain induced by nerve damage due to trauma or invasion of cancer to the bone elicits severe ongoing pain as well as hyperalgesia and allodynia likely reflecting adaptive changes within central circuits that amplify nociceptive signals. The present study explored the possible contribution of the mesolimbic dopaminergic circuit in promoting allodynia related to neuropathic and cancer pain. Mice with ligation of the sciatic nerve or treated with intrafemoral osteosarcoma cells showed allodynia to a thermal stimulus applied to the paw on the injured side. Patch clamp electrophysiology revealed that the intrinsic neuronal excitability of ventral tegmental area (VTA) dopamine neurons projecting to the nucleus accumbens (N.Acc.) was significantly reduced in those mice. We used tyrosine hydroxylase (TH)-cre mice that were microinjected with adeno-associated virus (AAV) to express channelrhodopsin-2 (ChR2) to allow optogenetic stimulation of VTA dopaminergic neurons in the VTA or in their N.Acc. terminals. Optogenetic activation of these cells produced a significant but transient anti-allodynic effect in nerve injured or tumor-bearing mice without increasing response thresholds to thermal stimulation in sham-operated animals. Suppressed activity of mesolimbic dopaminergic neurons is likely to contribute to decreased inhibition of N.Acc. output neurons and to neuropathic or cancer pain-induced allodynia suggesting strategies for modulation of pathological pain states.

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Expression pattern of EYA4 in the common marmoset (Callithrix jacchus) cochlea

Matsuzaki S., Hosoya M., Okano H., Fujioka M., Ogawa K.

Neuroscience Letters （Neuroscience Letters） 662 185 - 188 2018年01月

ISSN 03043940

© 2017 The eyes absent (EYA)-like genes are essential for the formation of sensory organs among fly (Drosophila melanogaster) and mammals. EYA4, one of the vertebrate genes of Eya family, is reported to be causative for late-onset mid-frequency sensorineural hearing loss in humans, while Eya4-deficient mice exhibited congenital profound deafness and otitis media with effusion due to the eustachian tube dysmorphology. Because of the species difference in the phenotype, the pathophysiology of EYA4 in the human cochlea has yet to be elucidated. Here, we examine the expression pattern of EYA4 in the cochlea of common marmoset (Callithrix jacchus), a non-human primate. The results indicated a distinct expression pattern of EYA4 in the adult marmoset cochleae, especially strong in all supporting cells, while in mouse their expressions were diminished. Interestingly, EYA4 expression in the hair cells, supporting cells and neurons was co-localized with sine oculis homeobox–SIX1, a transcription factor essential for the transcriptional activity of EYA4. The results revealed inter-species differences in the expression pattern of EYA4 gene in supporting cells between primates and rodents. The results also indicated a fundamental role of EYA4 in the primate auditory cells. Experiments with primate models such as marmosets or with human cochlear cells may provide cues about the unknown pathogenesis of EYA4-related hearing loss.

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Parkin absence accelerates microtubule aging in dopaminergic neurons

Cartelli D., Amadeo A., Calogero A., Casagrande F., De Gregorio C., Gioria M., Kuzumaki N., Costa I., Sassone J., Ciammola A., Hattori N., Okano H., Goldwurm S., Roybon L., Pezzoli G., Cappelletti G.

Neurobiology of Aging （Neurobiology of Aging） 61 66 - 74 2018年01月

ISSN 01974580

© 2017 Elsevier Inc. Loss-of-function caused by mutations in the parkin gene (PARK2) lead to early-onset familial Parkinson's disease. Recently, mechanistic studies proved the ability of parkin in regulating mitochondria homeostasis and microtubule (MT) stability. Looking at these systems during aging of PARK2 knockout mice, we found that loss of parkin induced an accelerated (over)acetylation of MT system both in dopaminergic neuron cell bodies and fibers, localized in the substantia nigra and corpus striatum, respectively. Interestingly, in PARK2 knockout mice, changes of MT stability preceded the alteration of mitochondria transport. Moreover, in-cell experiments confirmed that loss of parkin affects mitochondria mobility and showed that this defect depends on MT system as it is rescued by paclitaxel, a well-known MT-targeted agent. Furthermore, both in PC12 neuronal cells and in patients' induced pluripotent stem cell–derived midbrain neurons, we observed that parkin deficiencies cause the fragmentation of stable MTs. Therefore, we suggest that parkin acts as a regulator of MT system during neuronal aging, and we endorse the hypothesis that MT dysfunction may be crucial in the pathogenesis of Parkinson's disease.

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Chemical decontamination of iPS cell-derived neural cell mixtures

Mao D., Chung X., Andoh-Noda T., Qin Y., Sato S., Takemoto Y., Akamatsu W., Okano H., Uesugi M.

Chemical Communications （Chemical Communications） 54 （ 11 ） 1355 - 1358 2018年

ISSN 13597345

© 2018 The Royal Society of Chemistry. This report describes the design and evaluation of phosphorylated 7-ethyl-10-hydroxycamptothecin (SN38-P), which selectively eliminates tumor-forming proliferative stem cells, including human induced pluripotent stem cells (hiPSCs) and neural stem cells, from iPSC-derived neural cell mixtures. Results of the present study demonstrate that simple phosphorylation of an anticancer drug can provide a safe, cost-effective, and chemically-defined tool for decontaminating hiPSC-derived neuron.

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Astrocyte-derived exosomes treated with a semaphorin 3A inhibitor enhance stroke recovery via prostaglandin D <inf>2</inf> synthase

Hira K., Ueno Y., Tanaka R., Miyamoto N., Yamashiro K., Inaba T., Urabe T., Okano H., Hattori N.

Stroke （Stroke） 49 （ 10 ） 2483 - 2494 2018年

ISSN 00392499

© 2018 American Heart Association, Inc. Background and Purpose: Exosomes play a pivotal role in neurogenesis. In the peri-infarct area after stroke, axons begin to regenerate but are inhibited by astrocyte scar formation. The direct effect and underlying molecular mechanisms of astrocyte-derived exosomes on axonal outgrowth after ischemia are not known. Methods: Using a semaphorin 3A (Sema3A) inhibitor, we explored neuronal signaling during axonal outgrowth after ischemia in rats subjected to middle cerebral artery occlusion and in cultured cortical neurons challenged with oxygen-glucose deprivation. Furthermore, we assessed whether this inhibitor suppressed astrocyte activation and regulated astrocyte-derived exosomes to enhance axonal outgrowth after ischemia. Results: In rats subjected to middle cerebral artery occlusion, we administered a Sema3A inhibitor into the peri-infarct area from 7 to 21 days after occlusion. We found that phosphorylated high-molecular weight neurofilament-immunoreactive axons were increased, glial fibrillary acidic protein-immunoreactive astrocytes were decreased, and functional recovery was promoted at 28 days after middle cerebral artery occlusion. In cultured neurons, the Sema3A inhibitor decreased Rho family GTPase 1, increased R-Ras, which phosphorylates Akt and glycogen synthase kinase 3β (GSK-3β), selectively increased phosphorylated GSK-3β in axons, and thereby enhanced phosphorylated high-molecular weight neurofilament-immunoreactive axons after oxygen-glucose deprivation. In cultured astrocytes, the Sema3A inhibitor suppressed activation of astrocytes induced by oxygen-glucose deprivation. Exosomes secreted from ischemic astrocytes treated with the Sema3A inhibitor further promoted axonal elongation and increased prostaglandin D 2 synthase expression on microarray analysis. GSK-3β + and prostaglandin D 2 synthase + neurons were robustly increased after treatment with the Sema3A inhibitor in the peri-infarct area. Conclusions: Neuronal Rho family GTPase 1/R-Ras/Akt/GSK-3β signaling, axonal GSK-3β expression, and astrocyte-derived exosomes with prostaglandin D 2 synthase expression contribute to axonal outgrowth and functional recovery after stroke.

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Reactive astrocytes function as phagocytes after brain ischemia via ABCA1-mediated pathway

Morizawa Yosuke M., Hirayama Yuri, Ohno Noubuhiko, Shibata Shinsuke, Shigetomi Eiji, Sui Yang, Nabekura Junichi, Sato Koichi, Okajima Fumikazu, Takebayashi Hirohide, Okano Hideyuki, Koizumi Schuichi

Nature Communications 8 （ 1 ） 2017年12月

ISSN 2041-1723

Astrocytes become reactive following various brain insults; however, the functions of reactive astrocytes are poorly understood. Here, we show that reactive astrocytes function as phagocytes after transient ischemic injury and appear in a limited spatiotemporal pattern. Following transient brain ischemia, phagocytic astrocytes are observed within the ischemic penumbra region during the later stage of ischemia. However, phagocytic microglia are mainly observed within the ischemic core region during the earlier stage of ischemia. Phagocytic astrocytes upregulate ABCA1 and its pathway molecules, MEGF10 and GULP1, which are required for phagocytosis, and upregulation of ABCA1 alone is sufficient for enhancement of phagocytosis in vitro. Disrupting ABCA1 in reactive astrocytes result in fewer phagocytic inclusions after ischemia. Together, these findings suggest that astrocytes are transformed into a phagocytic phenotype as a result of increase in ABCA1 and its pathway molecules and contribute to remodeling of damaged tissues and penumbra networks.

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Regulation of Sema3c and the Interaction between Cardiac Neural Crest and Second Heart Field during Outflow Tract Development

Kodo Kazuki, Shibata Shinsuke, Miyagawa-Tomita Sachiko, Ong Sang Ging, Takahashi Hiroshi, Kume Tsutomu, Okano Hideyuki, Matsuoka Rumiko, Yamagishi Hiroyuki

Scientific Reports 7 （ 1 ） 2017年12月

ISSN 2045-2322

The cardiac neural crest cells (cNCCs) and the second heart field (SHF) play key roles in development of the cardiac outflow tract (OFT) for establishment of completely separated pulmonary and systemic circulations in vertebrates. A neurovascular guiding factor, Semaphorin 3c (Sema3c), is required for the development of the OFT, however, its regulation of the interaction between cNCCs and SHF remains to be determined. Here, we show that a Sema3c is a candidate that mediates interaction between cNCCs and the SHF during development of the OFT. Foxc1/c2 directly activates the transcription of Sema3c in the OFT, whereas, a hypomorph of Tbx1, a key SHF transcription factor, resulted in the ectopic expression of Sema3c in the pharyngeal arch region. Fgf8, a downstream secreted factor of Tbx1, inhibited the expression of Sema3c in cNCCs via activation of ERK1/2 signaling. Blocking of FGF8 caused ectopic expression of SEMA3C and a migration defect of cNCCs, resulting in abnormal chick pharyngeal arch development. These results suggest that proper spatio-temporal expression of Sema3c, regulated positively by Foxc1/c2 and negatively by the Tbx1-Fgf8 cascade, respectively, is essential for the interaction between cNCCs and the SHF that correctly navigates cNCCs towards the OFT, composed of SHF-derived cells.

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Visualization of migration of human cortical neurons generated from induced pluripotent stem cells

Bamba Yohei, Kanemura Yonehiro, Okano Hideyuki, Yamasaki Mami

Journal of Neuroscience Methods 289 57 - 63 2017年09月

ISSN 0165-0270

Background Neuronal migration is considered a key process in human brain development. However, direct observation of migrating human cortical neurons in the fetal brain is accompanied by ethical concerns and is a major obstacle in investigating human cortical neuronal migration. New method We established a novel system that enables direct visualization of migrating cortical neurons generated from human induced pluripotent stem cells (hiPSCs). Results We observed the migration of cortical neurons generated from hiPSCs derived from a control and from a patient with lissencephaly. Methods Our system needs no viable brain tissue, which is usually used in slice culture. Migratory behavior of human cortical neuron can be observed more easily and more vividly by its fluorescence and glial scaffold than that by earlier methods. Conclusions Our in vitro experimental system provides a new platform for investigating development of the human central nervous system and brain malformation.

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Evidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson's disease

Shiba-Fukushima Kahori, Ishikawa Kei Ichi, Inoshita Tsuyoshi, Izawa Nana, Takanashi Masashi, Sato Shigeto, Onodera Osamu, Akamatsu Wado, Okano Hideyuki, Imai Yuzuru, Hattori Nobutaka

Human Molecular Genetics 26 （ 16 ） 3172 - 3185 2017年08月

ISSN 0964-6906

The ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase Parkin, two gene products associated with young-onset Parkinson's disease (PD), participate in mitochondrial quality control. The phosphorylation of mitochondrial polyUb by PINK1, which is activated in a mitochondrial membrane potential (ΔΨm)-dependent manner, facilitates the mitochondrial translocation and concomitant enzymatic activation of Parkin, leading to the clearance of phospho-polyUb-tagged mitochondria via mitophagy. Thus, Ub phosphorylation is a key event in PINK1-Parkin-mediated mitophagy. Here, we examined the role of phospho-Ub signaling in the pathogenesis of PD using fly PD models, human brain tissue and dopaminergic neurons derived from induced pluripotent stem cells (iPSCs) containing Parkin or PINK1 mutations, as well as normal controls.We report that phospho-Ub signaling is highly conserved between humans and Drosophila, and that phospho-Ub signaling and the relocation of axonal mitochondria upon DWmreduction are indeed compromised in human dopaminergic neurons containing Parkin or PINK1 mutations. Moreover, phospho-Ub signaling is prominent in tyrosine hydroxylase-positive neurons compared with tyrosine hydroxylase-negative neurons, suggesting that PINK1-Parkin signaling is more required for dopaminergic neurons. These results shed light on the particular vulnerability of dopaminergic neurons to mitochondrial stress.

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