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

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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.