Tgfβ signaling regulates temporal neurogenesis and potency of neural stem cells in the CNS

Neuron. 2014 Dec 3;84(5):927-39. doi: 10.1016/j.neuron.2014.10.033. Epub 2014 Nov 13.

Abstract

How the sequential specification of neurons and progressive loss of potency associated with aging neural progenitors are regulated in vertebrate brain development is poorly understood. By examining a temporal differentiation lineage in the hindbrain, we here identify Tgfβ as a switch signal that executes the transition between early and late phases of neurogenesis and concurrently constrains progenitor potency. Young progenitors have inherent competence to produce late-born neurons, but implementation of late-differentiation programs requires suppression of early identity genes achieved through temporally programmed activation of Tgfβ downstream of Shh signaling. Unexpectedly, we find that sequentially occurring fate-switch decisions are temporally coupled, and onset of Tgfβ signaling appears thereby to impact on the overall lifespan of the temporal lineage. Our study establishes Tgfβ as a regulator of temporal identity and potency of neural stem cells, and provides proof of concept that Tgfβ can be applied to modulate temporal specification of neurons in stem cell engineering.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cell Movement / genetics
  • Cells, Cultured
  • Central Nervous System / cytology*
  • Chick Embryo
  • Embryo, Mammalian
  • Female
  • Gene Expression Regulation, Developmental / genetics
  • Gene Expression Regulation, Developmental / physiology*
  • Homeodomain Proteins / genetics
  • Mice
  • Mice, Transgenic
  • Neural Stem Cells / physiology*
  • Neural Tube
  • Neurogenesis / physiology*
  • Organ Culture Techniques
  • Pregnancy
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Transcription Factors / genetics
  • Zebrafish Proteins

Substances

  • Homeodomain Proteins
  • NBPhox protein
  • Nkx2.2 protein
  • Nkx6.2 protein, vertebrate
  • Receptors, Transforming Growth Factor beta
  • Transcription Factors
  • Zebrafish Proteins
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I