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  1. 020 学位論文
  2. 生命科学研究科
  3. 18 遺伝学専攻

The coupling mechanism to generate synchronized oscillation of segmentation clock in mouse

https://ir.soken.ac.jp/records/1693
https://ir.soken.ac.jp/records/1693
15e7d75b-b6a6-4f4c-894f-ad311333d470
名前 / ファイル ライセンス アクション
甲1347_要旨.pdf 要旨・審査要旨 (337.3 kB)
Item type 学位論文 / Thesis or Dissertation(1)
公開日 2011-01-19
タイトル
タイトル The coupling mechanism to generate synchronized oscillation of segmentation clock in mouse
タイトル
タイトル The coupling mechanism to generate synchronized oscillation of segmentation clock in mouse
言語 en
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 大久保, 佑亮

× 大久保, 佑亮

大久保, 佑亮

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フリガナ オオクボ, ユウスケ

× オオクボ, ユウスケ

オオクボ, ユウスケ

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著者 OKUBO, Yusuke

× OKUBO, Yusuke

en OKUBO, Yusuke

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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1347号
研究科
値 複合科学研究科
専攻
値 18 遺伝学専攻
学位授与年月日
学位授与年月日 2010-03-24
学位授与年度
値 2009
要旨
内容記述タイプ Other
内容記述 The body of vertebrates is composed of many repeated structures such as vertebrae,<br />ribs, skeletal muscles and subcutaneous tissues. These are based on transient<br />metameric structures, called somites, which are produced sequentially at certain<br />spatiotemporal intervals in an anterior to posterior sequence concomitant with the<br />posterior elongation of presomitic mesoderm (PSM). The periodicity is regulated by the<br />segmentation CLOCK which undergoes the oscillation of <i>Hes</i> gene expression under<br />the control of Notch signaling within a cell. The traveling wave of the CLOCK is<br />observed from the tail bud region and stops in the anterior PSM where a new somite is<br />generated. This waved pattern is generated by the change of gene expression in each<br />cell and not by cell movement. If the CLOCK oscillates among individual cells without<br />synchrony, the waved pattern will not be generated. Thus, it is required for the additional<br />mechanism which works in a non-cell-autonomous manner to synchronize the CLOCK<br />phase among neighboring cells.<br /><br /> In zebrafish, the CLOCK and its synchronization mechanism has been well<br />understood. A coupled oscillator model was proposed to link these two phenomena; it<br />has been explained that 1) INPUT receives OUTPUT from neighboring cells, 2)<br />Effectors of the CLOCK are activated by the INPUT and operate as CLOCK<br />components, 3) OUTPUT transmits information reflecting its own CLOCK phase to<br />neighboring cells. Therefore, they correct their CLOCKs each other by coupling their<br />CLOCKs. In the zebrafish somitogenesis, it was demonstrated that INPUT is Notch<br />signaling from Notch1a, the CLOCK is Her1/7 that shows oscillation via the<br />negative-feedback mechanism and OUTPUT is DeltaC oscillation controlled by Her1/7.<br /><br /> However, it has been difficult to reveal the synchronization mechanism in mouse<br />somitogenesis because the CLOCK itself disappears in a simple gene knockout mouse<br />that lacks function of Notch signaling, since Notch signal is a core component of the<br />CLOCK. Furthermore, the segmentation CLOCK components involved in the regulation<br />are more complicated in mice as compared with zebrafish. In the mouse PSM, Lfng, a<br />glycosyltransferase that is not implicated in zebrafish, oscillates upon activation by<br />Notch activity and repression by Hes7, and acts as a negative regulator for Notch<br />signaling via modifying Notch1 receptor. Hence, the cyclic expression of Lfng makes a<br />Notch signal oscillation as a segmentation CLOCK.<br /><br /> To reveal the mechanism to generate synchronized CLOCK oscillation in mice, I first<br />examined Dll1 expression pattern that works as an OUTPUT in zebrafish. The results<br />that Dll1 transcripts slightly oscillated in the PSM but its protein did not show clear<br />oscillation indicate that the OUTPUT mechanism of the coupling in mice is different from<br />that of zebrafish. Next, I performed mosaic embryo analyses to clarify the<br />synchronization mechanism. The mosaic analysis using wild-type and gene-knockout<br />(KO) cell is a powerful method to ask the mechanism involved in the cell-cell<br />communication. I conducted two types of mosaic embryo analyses using Dll1-null and<br />Lfng-null cells. If the coupled oscillator model via Notch signaling is utilized to generate<br />the synchronized CLOCK oscillation in mouse somitogenesis, it is thought that INPUT is<br />Notch signaling through Notch1 receptor, the CLOCK is the oscillation of Hes7 and<br />OUTPUT is an unknown factor through a transmitter Dll1. In Dll1-null mosaic embryos,<br />Dll1-KO cells do not have Dll1 which acts as a transmitter of the CLOCK to transmit its<br />own CLOCK state to neighboring cells but they have Notch1 (receiver). Therefore, I<br />expected that Dll1-KO cells must show incomplete coupling with neighboring wild-type<br />cell, but should not interfere synchronized oscillation of the CLOCK among wild-type<br />cells because Dll1-KO cells cannot transmit signals. I found that the CLOCK showed<br />abnormal pattern in Dll1-null mosaic embryos, however, it exhibited synchronized<br />oscillation to some degree. Therefore, the reduction of coupling cells may have caused<br />abnormal CLOCK pattern. On the other hand, CLOCK synchronization will be disrupted<br />in the Lfng-null mosaic embryo if Notch signal regulates synchronized CLOCK<br />oscillation through a coupling mechanism as zebrafish and if Lfng is involved in the<br />coupling mechanism. Lfng-null mosaic embryos showed severer defect in the<br />synchronized CLOCK oscillation compared with the Dll1-null mosaic embryos. These<br />results suggest that Notch signal also exhibits dual roles in the CLOCK and its<br />synchronization through the coupling mechanism as in the case of zebrafish.<br />Surprisingly, Lfng KO cells in Lfng-null mosaic embryos showed either positive or<br />negative Notch activity. This result was unexpected since Notch activity should be<br />up-regulated in the absence of Lfng as expected from the analysis of Lfng KO embryo.<br />Therefore, the oscillation of Notch activity in Lfng KO cells in Lfng-null mosaic embryos<br />must be caused by the presence of wild-type cells that have functional Lfng. These<br />results suggest that Lfng works on Notch signaling via not only <i>cis-</i> but also <i>trans-</i><br />regulation mechanisms and Dll1 activity might be regulated by Lfng. Accordingly, I<br />explored in detail the role of Lfng in the Notch signaling by co-culture experiments using<br />Notch signal reporter luciferase assay. The results indicate that Lfng alter the Notch<br />signaling activity by modifying Dll1 and Notch1.<br /><br /> In this study, I propose a new coupling mechanism to generate synchronized<br />oscillation of segmentation CLOCK in the mouse. It is possible to consider that Lfng can<br />work as the OUTPUT which retains/reflects CLOCK phase information and alters Notch<br />signaling to synchronize CLOCK phase among neighboring cells through the coupling<br />mechanism. Therefore, in mouse somitogenesis, the following five elements are<br />required for the coupling mechanism, 1) INPUT; Notch signaling, 2) CLOCK; the<br />oscillation of Hes7 expression, 3) OUTPUT; Lfng expression reflecting CLOCK phase<br />information, 4) transmitter; Dll1 and 5) receiver; Notchl. In mice, expressions of both<br />Dll1 and Notch1 are not regulated by the CLOCK.
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