The role of cis-inhibition during selection of the neural precursor cell

顺式抑制在神经前体细胞选择过程中的作用

• 批准号: 282706886
• 负责人: Professor Dr. Thomas Klein
• 金额: --
• 依托单位: Institut für Genetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/282706886?language=en
• 关键词: role; cis; inhibition; during; selection

Cis-inhibition is a mechanism that regulates the activity of the evolutionary conserved Notch pathway in a post-translational, concentration-dependent and cell-autonomous manner through its ligands. Both naturally occurring ligands of the Notch pathway in Drosophila, Delta (Dl) and Serrate (Ser), posses cis-inhibitory abilities. However, the structural basis of cis-inhibition is not understood. A classical process is mediated by the Notch pathway is lateral inhibition, which operates during early neurogenesis to select the neural precursor cells within an equivalence group termed proneural cluster (PNC) in Drosophila and mammals. Recent theoretical work suggests that cis-inhibition contributes to the fidelity of the lateral inhibition process. We have identified a Notch ligand that lacks the cis-inhibitory abilities and generated variants of the Delta ligand (Dl) that have increased cis-inhibitory abilities. These variants enable us to investigate the function of cis-inhibition during the selection of the neural precursors in two recently developed test systems in the wing imaginal disc. Moreover, these ligands enable us to investigate the structural basis of cis-inhibition. We observed differences among the two in Drosophila existing Notch ligands Dl and Serrate (Ser) in the ability to mediate the selection process. We will investigate the structural basis of these differences. The results of our experiments will reveal differences between the two ligands, which are the founders of the two subgroups of Notch ligands of the DSL family. They will also reveal the function of cis-inhibition during the fundamental process of lateral inhibition that operates also in mammals during neural precursor selection.

顺式抑制是一种机制，该机制通过其配体通过翻译后，浓度依赖性和细胞自治方式来调节进化保守的凹槽途径的活性。果蝇，三角洲（DL）和锯齿状（SER）的Notch途径的天然配体具有CIS抑制能力。但是，尚不清楚CIS抑制的结构基础。 Notch途径介导的经典过程是横向抑制作用，在早期神经发生过程中起作用，以在果蝇和哺乳动物中称为等效组中的神经前体细胞（PNC）中选择神经前体细胞。最近的理论工作表明，CIS抑制作用有助于横向抑制过程的保真度。我们已经确定了一种缺乏CIS抑制能力和产生的Delta配体（DL）变体的凹口配体，这些能力提高了CIS抑制能力。这些变体使我们能够在选择在翼想象中的两个最近开发的测试系统中选择神经前体期间的顺式抑制作用的功能。此外，这些配体使我们能够研究CIS抑制的结构基础。我们观察到果蝇中两者之间的差异在现有的Notch配体DL和锯齿状（SER）中介导了选择过程的能力。我们将研究这些差异的结构基础。我们的实验结果将揭示两个配体之间的差异，这是DSL家族的两个Notch配体子组的创始人。他们还将揭示在神经前体选择过程中在哺乳动物中也起作用的侧向抑制过程中CIS抑制作用的功能。