title: Control of Neural Daughter Cell Proliferation by Multi-level Notch/Su(H)/E(spl)-HLH Signaling.
abstract: 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.
authors.affiliation: Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Bivik
authors.affiliation: Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden.
authors.forename: Ryan B
authors.initials: RB
authors.lastname: MacDonald
authors.affiliation: Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden.
authors.forename: Erika
authors.initials: E
authors.lastname: Gunnar
authors.affiliation: Institut Pasteur, Paris, France.|CNRS, URA2578, Paris, France.
authors.forename: Khalil
authors.initials: K
authors.lastname: Mazouni
authors.affiliation: Institut Pasteur, Paris, France.|CNRS, URA2578, Paris, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Schweisguth
authors.affiliation: Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Thor
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D002450:Cell Communication / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism; D019070:Cell Lineage; D049109:Cell Proliferation / Q000235:genetics; D002490:Central Nervous System / Q000196:embryology*; D019927:Cyclin E / Q000378:metabolism; D004330:Drosophila / Q000196:embryology* / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism*; D050684:E2F Transcription Factors / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D009687:Nuclear Proteins / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D019927:Cyclin E; D029721:Drosophila Proteins; D050684:E2F Transcription Factors; D009687:Nuclear Proteins; D017027:Protein Tyrosine Phosphatases; D051880:Receptors, Notch; D012097:Repressor Proteins; D014157:Transcription Factors; C121960:E(spl)m7-HLH protein, Drosophila; C496298:E2f1 protein, Drosophila; C497759:N protein, Drosophila; C088731:Su(H) protein, Drosophila; C103336:dap protein, Drosophila; C059217:stg protein, Drosophila