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.

顺式抑制是通过其配体以翻译后、浓度依赖性和细胞自主性的方式调节进化上保守的Notch途径的活性的机制。果蝇中Notch途径的两种天然存在的配体Delta（Dl）和Serrate（Ser）具有顺式抑制能力。然而，顺式抑制的结构基础尚不清楚。由Notch通路介导的经典过程是侧抑制，其在早期神经发生期间操作以选择果蝇和哺乳动物中称为前神经簇（PNC）的等效组内的神经前体细胞。最近的理论工作表明，顺式抑制有助于侧抑制过程的保真度。我们已经鉴定了缺乏顺式抑制能力的Notch配体，并产生了具有增加的顺式抑制能力的Delta配体（Dl）的变体。这些变体使我们能够在最近开发的两个测试系统中的翼成虫盘的神经前体的选择过程中调查顺式抑制的功能。此外，这些配体使我们能够研究顺式抑制的结构基础。我们观察到在果蝇中存在的Notch配体Dl和Serrate（Ser）两者在介导选择过程的能力上的差异。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种配体之间的差异，这两种配体是DSL家族的两个Notch配体亚组的创始人。他们还将揭示在神经前体选择过程中也在哺乳动物中起作用的侧抑制的基本过程中顺式抑制的功能。