WEKO3
アイテム
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Thus, the construction of elaborated neural networks is indispensable for \u003cbr /\u003eexerting a normal brain functions. Brain development is categorized into several \u003cbr /\u003esteps such as neurogenesis, neuronal migration, axon projection, synaptogenesis, etc. \u003cbr /\u003eAmong them, neuronal migration is one of the most fundamental processes. If \u003cbr /\u003eneurons do not migrate directionally, the consequences wi11 be a chaotic brain \u003cbr /\u003ebecause numerous subtypes of neurons will be randomly intermixed. Neuronal \u003cbr /\u003emigration helps different neuronal populations to segregate into distinctive \u003cbr /\u003ecompartments, whereas it also contributes to the dispersion of one neurohal \u003cbr /\u003epopulation to occupy a large domain. In this way, distinct neuronal populations are \u003cbr /\u003eappropriately arranged in the brain, which enables the complicated brain functions. \u003cbr /\u003e Neurons migrate basically in two types of streams, radial and tangential. In the \u003cbr /\u003eradial migration, neurons migrate verdcally to the surface of a brain, whereas in the \u003cbr /\u003etangential migration, neurons migrate parallel to the surface. The radial migration is \u003cbr /\u003ea main migratory mode for constructing the six-layer cerebral cortex, and thus this \u003cbr /\u003emode have been well studied by many Laboratories for several decades. However, it \u003cbr /\u003ehas been only recently revealed that the tangential migration is also a critical \u003cbr /\u003emigratory stream for the brain development. The most famous example of the \u003cbr /\u003etangential migration is provided by GABA interneurons, which migrate from the \u003cbr /\u003eventral telencephalon towards the dorsal neocortex thorough the so-called \"dorsal\u003cbr /\u003etangential migration stream\". However, there is also a stream in the opposite \u003cbr /\u003edirection, \"ventral tangential migration\". Although this migration has been far less \u003cbr /\u003estudied compared with the dorsal tangential migration, there is a good model system \u003cbr /\u003efor analyzing the ventral tangential migration, which is lot cells. \u003cbr /\u003e Lot cells are a neuronal population recognized by monoclonal antibody (mAb) \u003cbr /\u003elot1. It has been revealed that these neurons are involved in the formation of the \u003cbr /\u003elateral olfactory tract (LOT), the fascicle of olfactory bulb axons extending on the \u003cbr /\u003esurface of the telencephalon. Our group previously reproted that newborn lot cells \u003cbr /\u003emigrate through the ventral tangential pathway. During the early developmental \u003cbr /\u003ephase at E9-10, lot cells differentiate from the ventricular zone of the dorsal \u003cbr /\u003eneocortex region, and migrate on the surface of the neocortex ventrally and \u003cbr /\u003etangentially. After finishing the migration, the cells accumulate at the presumptive \u003cbr /\u003eLOT region and make a cellular array, which guides or allows olfactory bulb axons to \u003cbr /\u003eform the accurate LOT. This migration pattern is quite unique from the viewpoint \u003cbr /\u003ethat the cell migration controls the following axon projection, but molecular \u003cbr /\u003emechanisms of the lot cell migration still remain unknown. \u003cbr /\u003e Our group previously performed combinational culture of early telencephalic \u003cbr /\u003eexplants, and suggested that the lot cell migration is non-cell autonomously \u003cbr /\u003econtrolled by multiple guidance cues; the neocortex region contains gradually \u003cbr /\u003edistributed guidance cues to orient the migrating cells into the ventral direction, \u003cbr /\u003ewhereas the ventral part of the telencephalon has some mechanisms to exclude lot \u003cbr /\u003ecells, probably mediated by short-range repulsive cues. An axon guidance molecule, \u003cbr /\u003eNetrin-1 has an attractive effect on the migration of lot cells in vitro. However, the \u003cbr /\u003eexpression of netrin-1 is only restricted in the ventral part of the telencephalon, .thus \u003cbr /\u003eNetrin-1 knockout mice exhibit only weak defects in the migration of lot cells. These \u003cbr /\u003eresults suggest that some other guidance molecules probably attract the lot cell \u003cbr /\u003emigration. Also the repulsive cues for lot cells, which should be essential for the final \u003cbr /\u003earrangement of the cells, were virtually unidentified. In order to understand \u003cbr /\u003emolecular mechanisms of the lot cell migration, I took two types of approaches; \u003cbr /\u003ecandidate screening and pharmacological perturbation. \u003cbr /\u003e First, I screened candidate guidance molecules. cDNAs for various guidance \u003cbr /\u003emolecules were transfected into HEK293T line cells, and the cell aggregates \u003cbr /\u003eexpressing the candidate molecules were made. Subsequently, the effects of candidate \u003cbr /\u003emolecules were investigated by co-culturing these cell aggregates with telencephalic \u003cbr /\u003eslices, after labeling the cells in the ventral tangential migration stream with a \u003cbr /\u003efluorescent dye, DiI. Among many candidate molecules, I found that a repulsive axon \u003cbr /\u003eguidance molecule, SemaphOrin3F had a repulsive effect on the lot cell migration. \u003cbr /\u003eSema3F receptor, Neuropilin-2, was expressed in lot cells, and Sema3F was \u003cbr /\u003e\u003cbr /\u003eexpressed in the region surrounding the presumptive LOT region. The cells in \u003cbr /\u003eNeuropilin-2 knockout mice did not respond to Sema3F in the culture system. I \u003cbr /\u003eexamined the distribution pattern of lot cells in Nrp2 knockout mice and found that \u003cbr /\u003esome lot cells were ectopically distributed in the medial region of the telencephalon. \u003cbr /\u003eThe majority of lot cells, however, normally aligned at the presumptive LOT region \u003cbr /\u003eand they did not cross over the presumptive LOT region ventrally. These results \u003cbr /\u003eindicate that Sema3F functions in confinement of lot cells on the surface of the \u003cbr /\u003eneocortex, but not exclusion of cells from the ventral telencephalon \u003cbr /\u003e Second, I tested various pharmacological drugs in culture, and found that a \u003cbr /\u003eprotein kinase inhibitor, K252a inhibits the migration of lot cells but does not inhibit \u003cbr /\u003ethe extension of leading processes. This result is interesting because it may provide a \u003cbr /\u003enew insight into the mechanisms of neuronal migration. Neurons usually migrate \u003cbr /\u003elong distances by the locomotion mode in which the leading processes and the cell \u003cbr /\u003ebody migrate in a coordinated manner. However, K252a seemed to convert this \u003cbr /\u003emigration mode into the neurite extension mode such as the axon projection or \u003cbr /\u003edendrite extension. Thus, I hoped that the effect of K252a would give an important \u003cbr /\u003eclue for understanding the switch of the migratory modes, and further analyzed this \u003cbr /\u003einteresting phenomenon in the time-lapse video microscopy to detail the kinetics of \u003cbr /\u003ethe effect. This analysis showed that K252a robustly decreased the migration speed \u003cbr /\u003eof cell bodies but not the extension of leading processes. K252a also converted the \u003cbr /\u003elocomotion mode of the cerebellar granule cells into the neurite extension mode, \u003cbr /\u003esuggesting that the switch of the migratory modes by K252a is rather a general \u003cbr /\u003ephenomenon observable in various neuronal populations. I found one drug, \u003cbr /\u003eroscovitine had a similar effect with K252a. Roscovitine is an inhibitor for cycling \u003cbr /\u003edependent kinases (CDK), and thus I overexpressed a dominant negative form of \u003cbr /\u003eneuronal CDK, CDK5 in migrating neurons. Overexpression of the dominant \u003cbr /\u003enegative CDK5 induced the extension of leading processes and slowdowned the \u003cbr /\u003emigration speed of cell bodies. Therefore, CDK5 activity may be one of the critical \u003cbr /\u003ecomponents for the switching of the migratory modes from the locomotion to the \u003cbr /\u003eneurite extension. \u003cbr /\u003e", "subitem_description_type": "Other"}]}, "item_1_description_7": {"attribute_name": "学位記番号", "attribute_value_mlt": [{"subitem_description": "総研大甲第1059号", "subitem_description_type": "Other"}]}, "item_1_select_14": {"attribute_name": "所蔵", "attribute_value_mlt": [{"subitem_select_item": "有"}]}, "item_1_select_8": {"attribute_name": "研究科", "attribute_value_mlt": [{"subitem_select_item": "生命科学研究科"}]}, "item_1_select_9": {"attribute_name": "専攻", "attribute_value_mlt": [{"subitem_select_item": "18 遺伝学専攻"}]}, "item_1_text_10": {"attribute_name": "学位授与年度", "attribute_value_mlt": [{"subitem_text_value": "2006"}]}, "item_creator": {"attribute_name": "著者", "attribute_type": "creator", "attribute_value_mlt": [{"creatorNames": [{"creatorName": "ITO, Keisuke", "creatorNameLang": "en"}], "nameIdentifiers": [{"nameIdentifier": "0", "nameIdentifierScheme": "WEKO"}]}]}, "item_files": {"attribute_name": "ファイル情報", "attribute_type": "file", "attribute_value_mlt": [{"accessrole": "open_date", "date": [{"dateType": "Available", "dateValue": "2016-02-17"}], "displaytype": "simple", "download_preview_message": "", "file_order": 0, "filename": "甲1059_要旨.pdf", "filesize": [{"value": "369.0 kB"}], "format": "application/pdf", "future_date_message": "", "is_thumbnail": false, "licensetype": "license_11", "mimetype": "application/pdf", "size": 369000.0, "url": {"label": "要旨・審査要旨", "url": "https://ir.soken.ac.jp/record/1030/files/甲1059_要旨.pdf"}, "version_id": "20cfb715-1163-4f9d-8662-806270411076"}]}, "item_language": {"attribute_name": "言語", "attribute_value_mlt": [{"subitem_language": "eng"}]}, "item_resource_type": {"attribute_name": "資源タイプ", "attribute_value_mlt": [{"resourcetype": "thesis", "resourceuri": "http://purl.org/coar/resource_type/c_46ec"}]}, "item_title": "Molecular mechanisms of ventral tangential migration of lot cells, the guide post neurons in the lateral olfactory tract", "item_titles": {"attribute_name": "タイトル", "attribute_value_mlt": [{"subitem_title": "Molecular mechanisms of ventral tangential migration of lot cells, the guide post neurons in the lateral olfactory tract"}, {"subitem_title": "Molecular mechanisms of ventral tangential migration of lot cells, the guide post neurons in the lateral olfactory tract", "subitem_title_language": "en"}]}, "item_type_id": "1", "owner": "1", "path": ["20"], "permalink_uri": "https://ir.soken.ac.jp/records/1030", "pubdate": {"attribute_name": "公開日", "attribute_value": "2010-02-22"}, "publish_date": "2010-02-22", "publish_status": "0", "recid": "1030", "relation": {}, "relation_version_is_last": true, "title": ["Molecular mechanisms of ventral tangential migration of lot cells, the guide post neurons in the lateral olfactory tract"], "weko_shared_id": 1}
Molecular mechanisms of ventral tangential migration of lot cells, the guide post neurons in the lateral olfactory tract
https://ir.soken.ac.jp/records/1030
https://ir.soken.ac.jp/records/1030999cad84-0e40-4a33-a13d-fb91a3102617
名前 / ファイル | ライセンス | アクション |
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Item type | 学位論文 / Thesis or Dissertation(1) | |||||
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公開日 | 2010-02-22 | |||||
タイトル | ||||||
タイトル | Molecular mechanisms of ventral tangential migration of lot cells, the guide post neurons in the lateral olfactory tract | |||||
タイトル | ||||||
言語 | en | |||||
タイトル | Molecular mechanisms of ventral tangential migration of lot cells, the guide post neurons in the lateral olfactory tract | |||||
言語 | ||||||
言語 | eng | |||||
資源タイプ | ||||||
資源タイプ識別子 | http://purl.org/coar/resource_type/c_46ec | |||||
資源タイプ | thesis | |||||
著者名 |
伊藤, 圭祐
× 伊藤, 圭祐 |
|||||
フリガナ |
イトウ, ケイスケ
× イトウ, ケイスケ |
|||||
著者 |
ITO, Keisuke
× ITO, Keisuke |
|||||
学位授与機関 | ||||||
学位授与機関名 | 総合研究大学院大学 | |||||
学位名 | ||||||
学位名 | 博士(理学) | |||||
学位記番号 | ||||||
内容記述タイプ | Other | |||||
内容記述 | 総研大甲第1059号 | |||||
研究科 | ||||||
値 | 生命科学研究科 | |||||
専攻 | ||||||
値 | 18 遺伝学専攻 | |||||
学位授与年月日 | ||||||
学位授与年月日 | 2007-03-23 | |||||
学位授与年度 | ||||||
2006 | ||||||
要旨 | ||||||
内容記述タイプ | Other | |||||
内容記述 | The brain functions are accomplished via communications between vast numbers of <br />neurons. Thus, the construction of elaborated neural networks is indispensable for <br />exerting a normal brain functions. Brain development is categorized into several <br />steps such as neurogenesis, neuronal migration, axon projection, synaptogenesis, etc. <br />Among them, neuronal migration is one of the most fundamental processes. If <br />neurons do not migrate directionally, the consequences wi11 be a chaotic brain <br />because numerous subtypes of neurons will be randomly intermixed. Neuronal <br />migration helps different neuronal populations to segregate into distinctive <br />compartments, whereas it also contributes to the dispersion of one neurohal <br />population to occupy a large domain. In this way, distinct neuronal populations are <br />appropriately arranged in the brain, which enables the complicated brain functions. <br /> Neurons migrate basically in two types of streams, radial and tangential. In the <br />radial migration, neurons migrate verdcally to the surface of a brain, whereas in the <br />tangential migration, neurons migrate parallel to the surface. The radial migration is <br />a main migratory mode for constructing the six-layer cerebral cortex, and thus this <br />mode have been well studied by many Laboratories for several decades. However, it <br />has been only recently revealed that the tangential migration is also a critical <br />migratory stream for the brain development. The most famous example of the <br />tangential migration is provided by GABA interneurons, which migrate from the <br />ventral telencephalon towards the dorsal neocortex thorough the so-called "dorsal<br />tangential migration stream". However, there is also a stream in the opposite <br />direction, "ventral tangential migration". Although this migration has been far less <br />studied compared with the dorsal tangential migration, there is a good model system <br />for analyzing the ventral tangential migration, which is lot cells. <br /> Lot cells are a neuronal population recognized by monoclonal antibody (mAb) <br />lot1. It has been revealed that these neurons are involved in the formation of the <br />lateral olfactory tract (LOT), the fascicle of olfactory bulb axons extending on the <br />surface of the telencephalon. Our group previously reproted that newborn lot cells <br />migrate through the ventral tangential pathway. During the early developmental <br />phase at E9-10, lot cells differentiate from the ventricular zone of the dorsal <br />neocortex region, and migrate on the surface of the neocortex ventrally and <br />tangentially. After finishing the migration, the cells accumulate at the presumptive <br />LOT region and make a cellular array, which guides or allows olfactory bulb axons to <br />form the accurate LOT. This migration pattern is quite unique from the viewpoint <br />that the cell migration controls the following axon projection, but molecular <br />mechanisms of the lot cell migration still remain unknown. <br /> Our group previously performed combinational culture of early telencephalic <br />explants, and suggested that the lot cell migration is non-cell autonomously <br />controlled by multiple guidance cues; the neocortex region contains gradually <br />distributed guidance cues to orient the migrating cells into the ventral direction, <br />whereas the ventral part of the telencephalon has some mechanisms to exclude lot <br />cells, probably mediated by short-range repulsive cues. An axon guidance molecule, <br />Netrin-1 has an attractive effect on the migration of lot cells in vitro. However, the <br />expression of netrin-1 is only restricted in the ventral part of the telencephalon, .thus <br />Netrin-1 knockout mice exhibit only weak defects in the migration of lot cells. These <br />results suggest that some other guidance molecules probably attract the lot cell <br />migration. Also the repulsive cues for lot cells, which should be essential for the final <br />arrangement of the cells, were virtually unidentified. In order to understand <br />molecular mechanisms of the lot cell migration, I took two types of approaches; <br />candidate screening and pharmacological perturbation. <br /> First, I screened candidate guidance molecules. cDNAs for various guidance <br />molecules were transfected into HEK293T line cells, and the cell aggregates <br />expressing the candidate molecules were made. Subsequently, the effects of candidate <br />molecules were investigated by co-culturing these cell aggregates with telencephalic <br />slices, after labeling the cells in the ventral tangential migration stream with a <br />fluorescent dye, DiI. Among many candidate molecules, I found that a repulsive axon <br />guidance molecule, SemaphOrin3F had a repulsive effect on the lot cell migration. <br />Sema3F receptor, Neuropilin-2, was expressed in lot cells, and Sema3F was <br /><br />expressed in the region surrounding the presumptive LOT region. The cells in <br />Neuropilin-2 knockout mice did not respond to Sema3F in the culture system. I <br />examined the distribution pattern of lot cells in Nrp2 knockout mice and found that <br />some lot cells were ectopically distributed in the medial region of the telencephalon. <br />The majority of lot cells, however, normally aligned at the presumptive LOT region <br />and they did not cross over the presumptive LOT region ventrally. These results <br />indicate that Sema3F functions in confinement of lot cells on the surface of the <br />neocortex, but not exclusion of cells from the ventral telencephalon <br /> Second, I tested various pharmacological drugs in culture, and found that a <br />protein kinase inhibitor, K252a inhibits the migration of lot cells but does not inhibit <br />the extension of leading processes. This result is interesting because it may provide a <br />new insight into the mechanisms of neuronal migration. Neurons usually migrate <br />long distances by the locomotion mode in which the leading processes and the cell <br />body migrate in a coordinated manner. However, K252a seemed to convert this <br />migration mode into the neurite extension mode such as the axon projection or <br />dendrite extension. Thus, I hoped that the effect of K252a would give an important <br />clue for understanding the switch of the migratory modes, and further analyzed this <br />interesting phenomenon in the time-lapse video microscopy to detail the kinetics of <br />the effect. This analysis showed that K252a robustly decreased the migration speed <br />of cell bodies but not the extension of leading processes. K252a also converted the <br />locomotion mode of the cerebellar granule cells into the neurite extension mode, <br />suggesting that the switch of the migratory modes by K252a is rather a general <br />phenomenon observable in various neuronal populations. I found one drug, <br />roscovitine had a similar effect with K252a. Roscovitine is an inhibitor for cycling <br />dependent kinases (CDK), and thus I overexpressed a dominant negative form of <br />neuronal CDK, CDK5 in migrating neurons. Overexpression of the dominant <br />negative CDK5 induced the extension of leading processes and slowdowned the <br />migration speed of cell bodies. Therefore, CDK5 activity may be one of the critical <br />components for the switching of the migratory modes from the locomotion to the <br />neurite extension. <br /> | |||||
所蔵 | ||||||
値 | 有 |