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

顺式抑制是一种通过配体以翻译后、浓度依赖和细胞自主的方式调节进化保守的Notch通路活性的机制。在果蝇中，Notch通路的两种天然配体Delta （Dl）和Serrate （Ser）都具有顺式抑制能力。然而，顺式抑制的结构基础尚不清楚。Notch通路介导的一个经典过程是侧抑制，它在果蝇和哺乳动物的早期神经发生过程中选择一个称为前神经簇（PNC）的等效组中的神经前体细胞。最近的理论研究表明，顺式抑制有助于侧抑制过程的保真度。我们已经确定了缺乏顺式抑制能力的Notch配体，并产生了具有增加顺式抑制能力的Delta配体（Dl）的变体。这些变异使我们能够研究顺式抑制的功能，在两个最近开发的测试系统中选择的神经前体在翼想象盘。此外，这些配体使我们能够研究顺式抑制的结构基础。我们观察到果蝇现有的Notch配体Dl和Serrate （Ser）在介导选择过程的能力上存在差异。我们将研究这些差异的结构基础。我们的实验结果将揭示这两个配体之间的差异，这两个配体是DSL家族Notch配体两个亚群的奠基人。他们还将揭示顺式抑制在侧抑制的基本过程中的作用，这种抑制在哺乳动物的神经前体选择过程中也起作用。

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.