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

PLoS Genet. 2016 Apr 12;12(4):e1005984. doi: 10.1371/journal.pgen.1005984. eCollection 2016 Apr.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Binding Sites / genetics
  • Cell Communication / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Lineage
  • Cell Proliferation / genetics
  • Central Nervous System / embryology*
  • Cyclin E / metabolism
  • Drosophila / embryology*
  • Drosophila / genetics
  • Drosophila / metabolism
  • Drosophila Proteins / metabolism*
  • E2F Transcription Factors / metabolism
  • Embryo, Nonmammalian / metabolism
  • Gene Expression Regulation, Developmental
  • Nuclear Proteins / metabolism
  • Protein Tyrosine Phosphatases / metabolism
  • Receptors, Notch / metabolism*
  • Repressor Proteins / metabolism*
  • Signal Transduction
  • Transcription Factors
  • Transcription, Genetic / genetics
  • Transcriptional Activation / genetics

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle Proteins
  • Cyclin E
  • Drosophila Proteins
  • E(spl)m7-HLH protein, Drosophila
  • E2F Transcription Factors
  • E2f1 protein, Drosophila
  • N protein, Drosophila
  • Nuclear Proteins
  • Receptors, Notch
  • Repressor Proteins
  • Su(H) protein, Drosophila
  • Transcription Factors
  • dap protein, Drosophila
  • Protein Tyrosine Phosphatases
  • stg protein, Drosophila

Grants and funding

This work was supported by the Knut and Alice Wallenberg Foundation, Research Grant: (KAW2012.0101, www.wallenberg.com/kaw/), Swedish Research Council, Research Grant: (VR-NT) (621-2010-5214, www.vr.se), and by the Swedish Cancer Foundation, Research Grant: (120531, www.cancerfonden.se). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.