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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

Mesp2 and Tbx6 cooperatively establish periodic patterns, coupled with the clock machinery during mouse somitogenesis

https://ir.soken.ac.jp/records/1044
https://ir.soken.ac.jp/records/1044
24ea8eb8-9dbb-4172-b930-26ed0da16034
名前 / ファイル ライセンス アクション
甲1162_要旨.pdf 要旨・審査要旨 (334.2 kB)
甲1162_本文.pdf 本文 (3.0 MB)
Item type 学位論文 / Thesis or Dissertation(1)
公開日 2010-02-22
タイトル
タイトル Mesp2 and Tbx6 cooperatively establish periodic patterns, coupled with the clock machinery during mouse somitogenesis
タイトル
タイトル Mesp2 and Tbx6 cooperatively establish periodic patterns, coupled with the clock machinery during mouse somitogenesis
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 荻沼, 政之

× 荻沼, 政之

荻沼, 政之

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フリガナ オギヌマ, マサユキ

× オギヌマ, マサユキ

オギヌマ, マサユキ

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著者 OGINUMA, Masayuki

× OGINUMA, Masayuki

en OGINUMA, Masayuki

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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1162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 2008-03-19
学位授与年度
値 2007
要旨
内容記述タイプ Other
内容記述 During mouse embryogenesis, many morphogenetic events occur sequentially <br />according to the scheduled time, indicating that these sequential events are linked <br />with the precise temporal regulation. Such regulations must exist throughout <br />embryogenesis to coordinate many developmental processes, although the molecular <br />nature coordinating such temporal regulation is largely unknown. <br />  The vertebrate body is subdivided into repeating segments along the <br />anterior-posterior (AP) axis. This segmental or metameric pattern is established early <br />in embryogenesis by the process of somitogenesis. Somites are blocks of paraxial <br />mesoderm cells that give rise to the axial skeleton and their associated muscles and <br />tendons, which retain a metameric pattern. During development, somitogenesis is <br />tightly coupled with axis elongation. Precursors of the somites, called presomitic <br />mesoderm (PSM), arise from the posterior end of embryo, called tail bud. Somites are <br />aligned along the neural tube, and budding off from the anterior-most end of the <br />unsegmented presomitic mesoderm at the regular time. Therefore, somitogenesis is an <br />event that occurs according to the scheduled time, and it is believed that somitogenesis <br />is under the precise control of temporal information. <br />  The timing of somitogenesis is regulated by the so-called `segmentation clock', <br />which is associated with a periodic activation of Notch signal pathway in PSM cells. <br />Notch signal .activates the target genes, Hes7 and L-fng. The transcription factor Hes7 <br />(hairy and enhancer of split 7) in turn represses own transcription as well as that of <br />L-fng, making negative feedback loops. L-fng encodes a glycosyltransferase that acts <br />as a negative regulator of Notch activity, which generates the oscillation of Notch <br />signal activity within the PSM. However, the oscillation itself does not make a <br />segmental boundary, as exemplified by a pendulum clock in which the correct time is <br />not provided by the rhythm of pendulum. This temporal information has therefore to <br />be accurately translated into a spatial pattern during somitogenesis. <br />  The basic helix-loop-helix (bHLH) protein Mesp2 is a crucial factor in this process. <br />Mesp2 expression is periodically observed only in the anterior PSM, and the anterior <br />border of the Mesp2 expression domain determines the next somite segmental border. <br />To understand dynamic expression of Mesp2, the enhancer sequence, which is required <br />for the expression in the PSM, has been mapped within 185bp upstream region in the 5' <br />flanking region of Mesp2 gene, and it has been shown that a T-box transcriptional <br />factor, Tbx6, directly binds to the enhancer elements, and is essential for the <br />activation of Mesp2. Furthermore, it is shown that Notch signaling synergistically <br />works with Tbx6 and enhances Mesp2 activation when these factors coexist. However, <br />since the enhancer analysis was mainly conducted using the cultured cell system, <br />mechanisms involved in the spatial restriction and periodic regulation of Mesp2 <br />expression remain elusive. <br />  In this study, I have employed high resolution fluorescent in situ hybridization in <br />conjunction with immunohistochemical methods to analyze sections derived from <br />single specimens. These methods have enabled me to determine the spatio-temporal <br />relationship among several factors involved in mouse somitogenesis. Initially I show <br />that the timing of Mesp2 expression is determined by the periodic waves of Notch <br />activity, indicating the temporal link between Notch signal oscillation and Mesp2 <br />transcription cycle. Next, I find that Tbx6 defines the anterior limit of Mesp2 <br />expression domain by serving as an important transcription activator. Intriguingly, <br />Mesp2 mRNA initially shares an identical anterior border, but that once translated, <br />the Mesp2 protein is found to suppress Tbx6 expression post-translationally. This was <br />strongly supported by the fact that Tbx6 protein expression was expanded to the <br />anterior somitic region in the Mesp2-null embryo without altering expression pattern <br />of the transcript. The negative regulation of the Tbx6 by Mesp2 is critically important <br />to set up the next anterior border of Mesp2 expression domain. These results indicate <br />that interactions of three factors, Mesp2, Tbx6 and Notch activity are critically <br />important to translate temporal information to the spatial patterning. I also find that <br />onset of Mesp2 transcription is intimately linked with the initiation of Notch signal <br />oscillation, indicating that the relationship of three factors appears to be established <br />in the early stage embryo via initial Notch oscillation. I further show that the lack of <br />FGF signaling results in the posterior shift of Mesp2 expression domain, indicating <br />that FGF signaling provides a spatial cue to position the posterior border of Mesp2 <br />expresslon. <br />  Furthermore, to reveal the mechanism of post-translational Tbx6 suppression <br />downstream of Mesp2, I tried to determine the domain of Tbx6 protein that was <br />required for the suppression process. I generated transgenic mice harboring several <br />types of Tbx6 protein that had truncation in several domains, under the control of <br />endogenous promoter and enhancers of Tbx6 using a BAC-base transgenic mouse <br />technology. These results indicate that the T-box domain containing a DNA-binding <br />motif, is essential and sufficient for the suppression of Tbx6 expression. In good <br />agreement with these results, I find that Mesp2 also suppresses the expression of <br />Brachyury, the other T-box factor protein, by the post-translational mechanism. <br />  Taken together, I conclude that Mesp2 is the final output signal by which the <br />temporal information from the segmentation clock is translated to the segmental <br />patterning, and reciprocal regulation between Mesp2 and Tbx6 creates the periodic <br />pattern during somitogenesis. <br />
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