Abstract
In the developing Drosophila central nervous system (CNS), neural progenitor (neuroblast [NB]) selection is gated by lateral inhibition, controlled by Notch signaling and proneural genes. However, proneural mutants still generate many NBs, indicating the existence of additional proneural genes. Moreover, recent studies reveal involvement of key epithelial-mesenchymal transition (EMT) genes in NB selection, but the regulatory interplay between Notch signaling and the EMT machinery is unclear. We find that SoxNeuro (SoxB family) and worniu (Snail family) are integrated with the Notch pathway, and constitute the missing proneural genes. Notch signaling, the proneural, SoxNeuro, and worniu genes regulate key EMT genes to orchestrate the NB selection process. Hence, we uncover an expanded lateral inhibition network for NB selection and demonstrate its link to key players in the EMT machinery. The evolutionary conservation of the genes involved suggests that the Notch-SoxB-Snail-EMT network may control neural progenitor selection in many other systems.
Highlights
The embryonic Drosophila melanogaster (Drosophila) central nervous system (CNS) has been a central model system for addressing the genetic mechanisms controlling neural progenitor specification
The transcription factors (TFs) encoded by the E(spl)-C in turn repress the basic helix-loop-helix (bHLH) proneural genes within the achaete-scute complex (AS-C), i.e., achaete, scute and lethal of scute (l’sc) (Giagtzoglou et al, 2003)
The lateral inhibition process underlying the selection of peripheral sensory organ precursors (SOPs) has been the subject of intense study and in many key aspects mirrors the NB selection process (Schweisguth, 2015)
Summary
The embryonic Drosophila melanogaster (Drosophila) CNS has been a central model system for addressing the genetic mechanisms controlling neural progenitor specification. In the canonical Notch lateral inhibition pathway, the Delta (Dl) ligand binds to the Notch receptor, and ubiquitination of Dl, by the E3 ligase Neuralized (Neur) (Deblandre et al, 2001; Lai et al, 2001; Pavlopoulos et al, 2001; Yeh et al, 2001), results in Dl endocytosis, which promotes the trans-activation of Notch This triggers Notch cleavage (NotchON), releasing the Notch intracellular domain (NICD), which enters the nucleus and forms a tripartite complex with the DNA binding factor Suppressor of Hairless [Su(H)] and the co-factor Mastermind (Mam) (Hori et al, 2013; Kopan and Ilagan, 2009).
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