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首页> 外文学位 >Notchless interacts with multiple signaling pathways during mouse peri-implantation development.
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Notchless interacts with multiple signaling pathways during mouse peri-implantation development.

机译：Notchless在小鼠围着植入过程中与多种信号通路相互作用。

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摘要

During peri-implantation, the embryo transitions from a suspension environment in the fallopian tubes to an adherent system within the uterus. Successful transition requires maternal and fetal signaling cascades that establish maternal-fetal boundaries. Failure is common, as ~ 25% of all human pregnancies terminate during these steps. A large-scale mutation study in mice produced two mutants (l11Jus1 and l11Jus4) that are excellent models of this transition. l11Jus1 and l11Jus4 contain missense mutations in the Notchless homolog 1 ( Drosophila) (Nle1) gene. NLE1 is thought to signal via the canonical NOTCH pathway in vertebrates. Although in invertebrates and lower vertebrates, NOTCH signaling directs cell fate prior to gastrulation, it is dispensable for gastrulation in mice. Moreover, in yeast and plants, which lack NOTCH signaling, Nle1 is crucial for ribosome biogenesis. These seemingly contradictory data led me to hypothesize that mutation of Nle1 causes a lethal trauma to the embryo that disrupts multiple signaling pathways during peri-implantation development. I present data that: 1. Refute the presumption that Nle1 functions as a negative regulator of NOTCH during pre-implantation development; 2. Demonstrate that mutations in Nle1 lead to mis-expression of several members of the Wnt pathway; and 3. Show that mutant embryos enter cell cycle arrest; when that fails, they undergo p53-mediated programmed cell death. To understand the trauma(s) that precipitated these lethal cascades, I discovered that Nle1 mutants display delays in ribosomal RNA processing and nucleogenesis. These results uncover novel functions for NLE1 in the ribosomal biogenesis, TRP53 and WNT pathways during mammalian embryonic development.
机译：在围植入期间，胚胎从输卵管中的悬浮环境过渡到子宫内的附着系统。成功的过渡需要建立母婴边界的母婴信号级联。失败很常见，因为约有25％的人类怀孕在这些步骤中终止。在小鼠中进行的大规模突变研究产生了两个突变体（11Jus1和11Jus4），它们是这种过渡的极好模型。 11Jus1和11Jus4在Notchless homolog 1（Drosophila）（Nle1）基因中包含错义突变。 NLE1被认为通过脊椎动物的典型NOTCH途径发出信号。尽管在无脊椎动物和低等脊椎动物中，NOTCH信号在促胃动之前指导细胞命运，但对于小鼠的促胃动却是必不可少的。此外，在缺少NOTCH信号的酵母和植物中，Nle1对于核糖体生物发生至关重要。这些看似矛盾的数据使我假设Nle1的突变会导致胚胎致死性损伤，从而在植入后的整个发育过程中破坏多种信号通路。我提供的数据是：1.驳斥了Nle1在植入前发育过程中充当NOTCH负调节剂的假设； 2.证明Nle1中的突变导致Wnt途径的几个成员的错误表达； 3.显示突变的胚胎进入细胞周期停滞；当失败时，它们会经历p53介导的程序性细胞死亡。为了了解造成这些致命级联反应的创伤，我发现Nle1突变体在核糖体RNA加工和成核过程中显示出延迟。这些结果揭示了NLE1在哺乳动物胚胎发育过程中在核糖体生物发生，TRP53和WNT途径中的新功能。

著录项

  • 作者

    Lo, Chiao-Ling.;

  • 作者单位

    Purdue University.;

  • 授予单位 Purdue University.;
  • 学科 Agriculture Animal Culture and Nutrition.;Biology Genetics.
  • 学位 Ph.D.
  • 年度 2013
  • 页码 157 p.
  • 总页数 157
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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