Cortical Neurogenesis Requires Bcl6-Mediated Transcriptional Repression of Multiple Self-Renewal-Promoting Extrinsic Pathways

Neuron. 2019 Sep 25;103(6):1096-1108.e4. doi: 10.1016/j.neuron.2019.06.027. Epub 2019 Jul 25.

Abstract

During neurogenesis, progenitors switch from self-renewal to differentiation through the interplay of intrinsic and extrinsic cues, but how these are integrated remains poorly understood. Here, we combine whole-genome transcriptional and epigenetic analyses with in vivo functional studies to demonstrate that Bcl6, a transcriptional repressor previously reported to promote cortical neurogenesis, acts as a driver of the neurogenic transition through direct silencing of a selective repertoire of genes belonging to multiple extrinsic pathways promoting self-renewal, most strikingly the Wnt pathway. At the molecular level, Bcl6 represses its targets through Sirt1 recruitment followed by histone deacetylation. Our data identify a molecular logic by which a single cell-intrinsic factor represses multiple extrinsic pathways that favor self-renewal, thereby ensuring robustness of neuronal fate transition.

Keywords: Bcl6; FGF signaling; Notch signaling; SHH signaling; Wnt signaling; brain development; cyclins; neurogenesis; stemness; transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Self Renewal / genetics*
  • Epigenetic Repression / genetics*
  • Fibroblast Growth Factors / metabolism
  • Gene Expression Profiling
  • Hedgehog Proteins / metabolism
  • Histone Code
  • Histones / metabolism*
  • Mice
  • Neural Stem Cells / metabolism*
  • Neurogenesis / genetics*
  • Proto-Oncogene Proteins c-bcl-6 / genetics*
  • Proto-Oncogene Proteins c-bcl-6 / metabolism
  • RNA-Seq
  • Receptors, Notch / metabolism
  • Signal Transduction / genetics
  • Sirtuin 1 / metabolism*
  • Wnt Signaling Pathway / genetics

Substances

  • Bcl6 protein, mouse
  • Hedgehog Proteins
  • Histones
  • Proto-Oncogene Proteins c-bcl-6
  • Receptors, Notch
  • Shh protein, mouse
  • Fibroblast Growth Factors
  • Sirt1 protein, mouse
  • Sirtuin 1