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首页> 外文学位 >Study of neural tube closure using forward genetic screens in mice: Novel insight into Rb and cell cycle regulation, and enteric neural crest migration by PP1 and actin interacting protein.
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Study of neural tube closure using forward genetic screens in mice: Novel insight into Rb and cell cycle regulation, and enteric neural crest migration by PP1 and actin interacting protein.

机译：在小鼠中使用正向遗传筛选对神经管闭合的研究：对Rb和细胞周期调控的新见解，以及PP1和肌动蛋白相互作用蛋白对肠道神经c的迁移。

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摘要

One of the most exciting questions in developmental biology is how the nervous system is established and interconnected to form the central nervous system (CNS) and the peripheral nervous system (PNS), the latter which originates from the neural crest, which migrate away from the dorsal aspect of the neural tube. One of the key steps in neural development involves a complex morphogenesic process to close the neural tube. Defects in neural tube closure in humans are among the most prevalent of congenital malformations with an incidence of 1 out of every 1000 births. To study neural tube closure, we undertook a forward genetic ethylnitrosurea (ENU) screen in mice. We identified a variety of mouse mutants from the screen that displayed defects in neural morphogenesis and patterning. Here, I focus on the humpty dumpty (humdy) mutant line that displays defects in neural tube, eye, and enteric nervous system (ENS) development. To determine the gene whose function is required during embryogenesis to regulate the development of these tissues, I cloned the humdy mutant gene. The humdy gene encodes Phactr4, a novel Protein Phosphatase 1 (PP1) and actin regulator family member. The humdy allele carries a missense mutation which changes Arginine (Arg) to Proline (Pro) in the conserved C-terminal region. Moreover, this mutation disrupts PP1 binding but not actin binding.;In the studies described in Chapter 2, I investigated the mechanistic basis of the defect in neural tube closure (exencephaly) and in optic fissure closure (coloboma). Phactr4 is normally expressed in the neural tube and retina and, in the humdy mutant embryos, there was greatly increased proliferation and reduced differentiation in these tissues. Regulated proliferation is particularly striking at E9.5, where there is much less proliferation in the ventral half of the neural tube, where Phactr4 is most strongly expressed, relative to the dorsal half.;In the second set of studies described in Chapter 3, I have explored another phenotype in humdy mutant embryos with relevance to human birth defects. Hirschsprung disease patients have defects in the formation of the Enteric Nervous System (ENS) and this leads to an inability to properly move material through the gut. Humdy mutant embryos display a very similar intestinal defect due to a reduced number of ENS cells in the gut. (Abstract shortened by UMI.).
机译：发育生物学中最令人兴奋的问题之一是神经系统如何建立并相互连接以形成中枢神经系统（CNS）和周围神经系统（PNS），后者起源于神经rest，而神经c从神经the迁移而来。神经管的背面。神经发育的关键步骤之一涉及复杂的形态发生过程以闭合神经管。人的神经管闭合缺陷是最普遍的先天畸形，每千名新生儿中就有1名发生。为了研究神经管闭合，我们在小鼠中进行了正向遗传乙基亚硝基脲（ENU）筛查。我们从屏幕上发现了多种小鼠突变体，这些突变体在神经形态发生和模式上显示出缺陷。在这里，我重点介绍在神经管，眼睛和肠神经系统（ENS）发育中表现出缺陷的矮胖（矮胖）突变株。为了确定在胚胎发生过程中需要其功能来调节这些组织发育的基因，我克隆了谦卑的突变基因。谦卑的基因编码Phactr4，一种新型的蛋白磷酸酶1（PP1）和肌动蛋白调节剂家族成员。谦逊的等位基因携带一个错义突变，在保守的C端区域将精氨酸（Arg）变为脯氨酸（Pro）。而且，这种突变破坏了PP1的结合，但不破坏肌动蛋白的结合。在第2章描述的研究中，我研究了神经管闭合（无脑）和视裂闭合（结肠炎）缺陷的机制基础。 Phactr4通常在神经管和视网膜中表达，在谦卑的突变体胚胎中，这些组织中的增殖和分化大大降低。调节的增殖在E9.5处尤为明显，相对于背侧，E9.5在神经管的腹侧一半中的增殖要少得多，而Phactr4的表达最为强烈;在第二章研究中，我探索了与人类先天缺陷有关的谦逊突变胚胎中的另一种表型。巨结肠疾病患者的肠神经系统（ENS）形成有缺陷，这导致无法正确地通过肠道移动材料。由于肠道中的ENS细胞数量减少，Humdy突变体胚胎显示出非常相似的肠道缺陷。 （摘要由UMI缩短。）。

著录项

  • 作者

    Kim, Tae-Hee.;

  • 作者单位

    Weill Medical College of Cornell University.;

  • 授予单位 Weill Medical College of Cornell University.;
  • 学科 Biology Neuroscience.;Biology Cell.;Biology Genetics.
  • 学位 Ph.D.
  • 年度 2006
  • 页码 116 p.
  • 总页数 116
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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