Control of Neural Daughter Cell Proliferation by Multi-level Notch/Su(H)/E(spl)-HLH Signaling

The Notch pathway controls proliferation during development and in adulthood, and is frequently affected in many disorders. However, the genetic sensitivity and multi-layered transcriptional properties of the Notch pathway has made its molecular decoding challenging. Here, we address the complexity of Notch signaling with respect to proliferation, using the developing Drosophila CNS as model. We find that a Notch/Su(H)/E(spl)-HLH cascade specifically controls daughter, but not progenitor proliferation. Additionally, we find that different E(spl)-HLH genes are required in different neuroblast lineages. The Notch/Su(H)/E(spl)-HLH cascade alters daughter proliferation by regulating four key cell cycle factors: Cyclin E, String/Cdc25, E2f and Dacapo (mammalian p21CIP1/p27KIP1/p57Kip2). ChIP and DamID analysis of Su(H) and E(spl)-HLH indicates direct transcriptional regulation of the cell cycle genes, and of the Notch pathway itself. These results point to a multi-level signaling model and may help shed light on the dichotomous proliferative role of Notch signaling in many other systems

The pattern of transcription of the neurogenic gene Delta of Drosophila melanogaster

The function of the Delta locus of Drosophila melanogaster is required for the correct separation of neural and epidermal cell lineages. We describe here the transcriptional organization of this locus and the spatial pattern of mRNA accumulation during embryogenesis. Delta produces three mRNAs with protein-coding capacity, which differ only at their untranslated 3′ ends and thus encode the same protein; other minor RNAs from the locus are shown not to have any protein-coding capacity and to correspond to introns. No indications were obtained for multiple translational products of the locus. In situ hybridization using digoxigenin-labelled probes confirms that Delta RNA is present at high concentration in all presumptive neurogenic territories of the embryo. Since all the constituent cells of these territories contain Delta RNA, a differential distribution of the protein among the derivatives of the neuroectodermal cells is improbable. Some time after segregation of lineages, Delta RNA reappears in neuroblasts. The possible significance of these observations with respect to the function of the Delta product during lineage segregation is discussed.</jats:p