A regulatory transcriptional loop controls proliferation and differentiation in Drosophila neural stem cells

PLoS One. 2014 May 7;9(5):e97034. doi: 10.1371/journal.pone.0097034. eCollection 2014.

Abstract

Neurogenesis is initiated by a set of basic Helix-Loop-Helix (bHLH) transcription factors that specify neural progenitors and allow them to generate neurons in multiple rounds of asymmetric cell division. The Drosophila Daughterless (Da) protein and its mammalian counterparts (E12/E47) act as heterodimerization factors for proneural genes and are therefore critically required for neurogenesis. Here, we demonstrate that Da can also be an inhibitor of the neural progenitor fate whose absence leads to stem cell overproliferation and tumor formation. We explain this paradox by demonstrating that Da induces the differentiation factor Prospero (Pros) whose asymmetric segregation is essential for differentiation in one of the two daughter cells. Da co-operates with the bHLH transcription factor Asense, whereas the other proneural genes are dispensible. After mitosis, Pros terminates Asense expression in one of the two daughter cells. In da mutants, pros is not expressed, leading to the formation of lethal transplantable brain tumors. Our results define a transcriptional feedback loop that regulates the balance between self-renewal and differentiation in Drosophila optic lobe neuroblasts. They indicate that initiation of a neural differentiation program in stem cells is essential to prevent tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Carcinogenesis / genetics
  • Cell Differentiation / genetics*
  • Cell Proliferation / genetics
  • Drosophila
  • Drosophila Proteins / biosynthesis*
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Gene Expression Regulation, Developmental
  • Humans
  • Mitosis
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neural Stem Cells / metabolism*
  • Neurogenesis / genetics
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription, Genetic*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Da protein, Drosophila
  • Drosophila Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Transcription Factors
  • ase protein, Drosophila
  • pros protein, Drosophila

Grant support

Work in J.A.K.'s laboratory is supported by the Austrian Academy of Sciences, the Austrian Science Fund (FWF, grants I1281-B19 and Z_153_B09) and an advanced grant of the European Research Council (ERC). Support for T.Y. was provided by EMBO long-term fellowship and JSPS Postdoctoral Fellowship for Research Abroad. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.