{"_buckets": {"deposit": "8b4a4923-cdbc-4899-90f6-49081853df0e"}, "_deposit": {"created_by": 1, "id": "1044", "owners": [1], "pid": {"revision_id": 0, "type": "depid", "value": "1044"}, "status": "published"}, "_oai": {"id": "oai:ir.soken.ac.jp:00001044", "sets": ["20"]}, "author_link": ["0", "0", "0"], "item_1_biblio_info_21": {"attribute_name": "書誌情報（ソート用）", "attribute_value_mlt": [{"bibliographicIssueDates": {"bibliographicIssueDate": "2008-03-19", "bibliographicIssueDateType": "Issued"}, "bibliographic_titles": [{}]}]}, "item_1_creator_2": {"attribute_name": "著者名", "attribute_type": "creator", "attribute_value_mlt": [{"creatorNames": [{"creatorName": "荻沼, 政之"}], "nameIdentifiers": [{"nameIdentifier": "0", "nameIdentifierScheme": "WEKO"}]}]}, "item_1_creator_3": {"attribute_name": "フリガナ", "attribute_type": "creator", "attribute_value_mlt": [{"creatorNames": [{"creatorName": "オギヌマ, マサユキ"}], "nameIdentifiers": [{"nameIdentifier": "0", "nameIdentifierScheme": "WEKO"}]}]}, "item_1_date_granted_11": {"attribute_name": "学位授与年月日", "attribute_value_mlt": [{"subitem_dategranted": "2008-03-19"}]}, "item_1_degree_grantor_5": {"attribute_name": "学位授与機関", "attribute_value_mlt": [{"subitem_degreegrantor": [{"subitem_degreegrantor_name": "総合研究大学院大学"}]}]}, "item_1_degree_name_6": {"attribute_name": "学位名", "attribute_value_mlt": [{"subitem_degreename": "博士（理学）"}]}, "item_1_description_1": {"attribute_name": "ID", "attribute_value_mlt": [{"subitem_description": "2008055", "subitem_description_type": "Other"}]}, "item_1_description_12": {"attribute_name": "要旨", "attribute_value_mlt": [{"subitem_description": "　　During mouse embryogenesis, many morphogenetic events occur sequentially \u003cbr /\u003eaccording to the scheduled time, indicating that these sequential events are linked \u003cbr /\u003ewith the precise temporal regulation. Such regulations must exist throughout \u003cbr /\u003eembryogenesis to coordinate many developmental processes, although the molecular \u003cbr /\u003enature coordinating such temporal regulation is largely unknown. \u003cbr /\u003e　　The vertebrate body is subdivided into repeating segments along the \u003cbr /\u003eanterior-posterior (AP) axis. This segmental or metameric pattern is established early \u003cbr /\u003ein embryogenesis by the process of somitogenesis. Somites are blocks of paraxial \u003cbr /\u003emesoderm cells that give rise to the axial skeleton and their associated muscles and \u003cbr /\u003etendons, which retain a metameric pattern. During development, somitogenesis is \u003cbr /\u003etightly coupled with axis elongation. Precursors of the somites, called presomitic \u003cbr /\u003emesoderm (PSM), arise from the posterior end of embryo, called tail bud. Somites are \u003cbr /\u003ealigned along the neural tube, and budding off from the anterior-most end of the \u003cbr /\u003eunsegmented presomitic mesoderm at the regular time. Therefore, somitogenesis is an \u003cbr /\u003eevent that occurs according to the scheduled time, and it is believed that somitogenesis \u003cbr /\u003eis under the precise control of temporal information. \u003cbr /\u003e　　The timing of somitogenesis is regulated by the so-called `segmentation clock\u0027, \u003cbr /\u003ewhich is associated with a periodic activation of Notch signal pathway in PSM cells. \u003cbr /\u003eNotch signal .activates the target genes, Hes7 and L-fng. The transcription factor Hes7 \u003cbr /\u003e(hairy and enhancer of split 7) in turn represses own transcription as well as that of \u003cbr /\u003eL-fng, making negative feedback loops. L-fng encodes a glycosyltransferase that acts \u003cbr /\u003eas a negative regulator of Notch activity, which generates the oscillation of Notch \u003cbr /\u003esignal activity within the PSM. However, the oscillation itself does not make a \u003cbr /\u003esegmental boundary, as exemplified by a pendulum clock in which the correct time is \u003cbr /\u003enot provided by the rhythm of pendulum. This temporal information has therefore to \u003cbr /\u003ebe accurately translated into a spatial pattern during somitogenesis. \u003cbr /\u003e　　The basic helix-loop-helix (bHLH) protein Mesp2 is a crucial factor in this process. \u003cbr /\u003eMesp2 expression is periodically observed only in the anterior PSM, and the anterior \u003cbr /\u003eborder of the Mesp2 expression domain determines the next somite segmental border. \u003cbr /\u003eTo understand dynamic expression of Mesp2, the enhancer sequence, which is required \u003cbr /\u003efor the expression in the PSM, has been mapped within 185bp upstream region in the 5\u0027 \u003cbr /\u003eflanking region of Mesp2 gene, and it has been shown that a T-box transcriptional \u003cbr /\u003efactor, Tbx6, directly binds to the enhancer elements, and is essential for the \u003cbr /\u003eactivation of Mesp2. Furthermore, it is shown that Notch signaling synergistically \u003cbr /\u003eworks with Tbx6 and enhances Mesp2 activation when these factors coexist. However, \u003cbr /\u003esince the enhancer analysis was mainly conducted using the cultured cell system, \u003cbr /\u003emechanisms involved in the spatial restriction and periodic regulation of Mesp2 \u003cbr /\u003eexpression remain elusive. \u003cbr /\u003e　　In this study, I have employed high resolution fluorescent in situ hybridization in \u003cbr /\u003econjunction with immunohistochemical methods to analyze sections derived from \u003cbr /\u003esingle specimens. These methods have enabled me to determine the spatio-temporal \u003cbr /\u003erelationship among several factors involved in mouse somitogenesis. Initially I show \u003cbr /\u003ethat the timing of Mesp2 expression is determined by the periodic waves of Notch \u003cbr /\u003eactivity, indicating the temporal link between Notch signal oscillation and Mesp2 \u003cbr /\u003etranscription cycle. Next, I find that Tbx6 defines the anterior limit of Mesp2 \u003cbr /\u003eexpression domain by serving as an important transcription activator. Intriguingly, \u003cbr /\u003eMesp2 mRNA initially shares an identical anterior border, but that once translated, \u003cbr /\u003ethe Mesp2 protein is found to suppress Tbx6 expression post-translationally. This was \u003cbr /\u003estrongly supported by the fact that Tbx6 protein expression was expanded to the \u003cbr /\u003eanterior somitic region in the Mesp2-null embryo without altering expression pattern \u003cbr /\u003eof the transcript. The negative regulation of the Tbx6 by Mesp2 is critically important \u003cbr /\u003eto set up the next anterior border of Mesp2 expression domain. These results indicate \u003cbr /\u003ethat interactions of three factors, Mesp2, Tbx6 and Notch activity are critically \u003cbr /\u003eimportant to translate temporal information to the spatial patterning. I also find that \u003cbr /\u003eonset of Mesp2 transcription is intimately linked with the initiation of Notch signal \u003cbr /\u003eoscillation, indicating that the relationship of three factors appears to be established \u003cbr /\u003ein the early stage embryo via initial Notch oscillation. I further show that the lack of \u003cbr /\u003eFGF signaling results in the posterior shift of Mesp2 expression domain, indicating \u003cbr /\u003ethat FGF signaling provides a spatial cue to position the posterior border of Mesp2 \u003cbr /\u003eexpresslon. \u003cbr /\u003e　　Furthermore, to reveal the mechanism of post-translational Tbx6 suppression \u003cbr /\u003edownstream of Mesp2, I tried to determine the domain of Tbx6 protein that was \u003cbr /\u003erequired for the suppression process. I generated transgenic mice harboring several \u003cbr /\u003etypes of Tbx6 protein that had truncation in several domains, under the control of \u003cbr /\u003eendogenous promoter and enhancers of Tbx6 using a BAC-base transgenic mouse \u003cbr /\u003etechnology. These results indicate that the T-box domain containing a DNA-binding \u003cbr /\u003emotif, is essential and sufficient for the suppression of Tbx6 expression. In good \u003cbr /\u003eagreement with these results, I find that Mesp2 also suppresses the expression of \u003cbr /\u003eBrachyury, the other T-box factor protein, by the post-translational mechanism. \u003cbr /\u003e　　Taken together, I conclude that Mesp2 is the final output signal by which the \u003cbr /\u003etemporal information from the segmentation clock is translated to the segmental \u003cbr /\u003epatterning, and reciprocal regulation between Mesp2 and Tbx6 creates the periodic \u003cbr /\u003epattern during somitogenesis. \u003cbr /\u003e", "subitem_description_type": "Other"}]}, "item_1_description_18": {"attribute_name": "フォーマット", "attribute_value_mlt": [{"subitem_description": "application/pdf", "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1162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": "2007"}]}, "item_creator": {"attribute_name": "著者", "attribute_type": "creator", "attribute_value_mlt": [{"creatorNames": [{"creatorName": "OGINUMA, Masayuki", "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1162_要旨.pdf", "filesize": [{"value": "334.2 kB"}], "format": "application/pdf", "future_date_message": "", "is_thumbnail": false, "licensetype": "license_11", "mimetype": "application/pdf", "size": 334200.0, "url": {"label": "要旨・審査要旨", "url": "https://ir.soken.ac.jp/record/1044/files/甲1162_要旨.pdf"}, "version_id": "ef6be7c8-3c9a-4cda-a026-507181b241c7"}, {"accessrole": "open_date", "date": [{"dateType": "Available", "dateValue": "2016-02-17"}], "displaytype": "simple", "download_preview_message": "", "file_order": 1, "filename": "甲1162_本文.pdf", "filesize": [{"value": "3.0 MB"}], "format": "application/pdf", "future_date_message": "", "is_thumbnail": false, "licensetype": "license_11", "mimetype": "application/pdf", "size": 3000000.0, "url": {"label": "本文", "url": "https://ir.soken.ac.jp/record/1044/files/甲1162_本文.pdf"}, "version_id": "bd18617f-4186-45d4-8547-40f43b1db895"}]}, "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": "Mesp2 and Tbx6 cooperatively establish periodic patterns, coupled with the clock machinery during mouse somitogenesis", "item_titles": {"attribute_name": "タイトル", "attribute_value_mlt": [{"subitem_title": "Mesp2 and Tbx6 cooperatively establish periodic patterns, coupled with the clock machinery during mouse somitogenesis"}, {"subitem_title": "Mesp2 and Tbx6 cooperatively establish periodic patterns, coupled with the clock machinery during mouse somitogenesis", "subitem_title_language": "en"}]}, "item_type_id": "1", "owner": "1", "path": ["20"], "permalink_uri": "https://ir.soken.ac.jp/records/1044", "pubdate": {"attribute_name": "公開日", "attribute_value": "2010-02-22"}, "publish_date": "2010-02-22", "publish_status": "0", "recid": "1044", "relation": {}, "relation_version_is_last": true, "title": ["Mesp2 and Tbx6 cooperatively establish periodic patterns, coupled with the clock machinery during mouse somitogenesis"], "weko_shared_id": -1}