Soluble Jagged1 attenuates lateral inhibition, allowing for the clonal expansion of neural crest stem cells

Stem Cells. 2007 Dec;25(12):3133-42. doi: 10.1634/stemcells.2007-0327. Epub 2007 Aug 30.

Abstract

The activation of Notch signaling in neural crest stem cells (NCSCs) results in the rapid loss of neurogenic potential and differentiation into glia. We now show that the attenuation of endogenous Notch signaling within expanding NCSC clones by the Notch ligand soluble Jagged1 (sJ1), maintains NCSCs in a clonal self-renewing state in vitro without affecting their sensitivity to instructive differentiation signals observed previously during NCSC self-renewal. sJ1 functions as a competitive inhibitor of Notch signaling to modulate endogenous cell-cell communication to levels sufficient to inhibit neural differentiation but insufficient to instruct gliogenic differentiation. Attenuated Notch signaling promotes the induction and nonclassic release of fibroblast growth factor 1 (FGF1). The functions of sJ1 and FGF1 signaling are complementary, as abrogation of FGF signaling diminishes the ability of sJ1 to promote NCSC expansion, yet the secondary NCSCs maintain the dosage sensitivity of the founder. These results validate and build upon previous studies on the role of Notch signaling in stem cell self-renewal and suggest that the differentiation bias or self-renewal potential of NCSCs is intrinsically linked to the level of endogenous Notch signaling. This should provide a unique opportunity for the expansion of NCSCs ex vivo without altering their differentiation bias for clinical cell replacement or transplant strategies in tissue repair. Disclosure of potential conflicts of interest is found at the end of this article.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / physiology*
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology*
  • Cell Proliferation
  • Cells, Cultured
  • Clone Cells / cytology
  • Clone Cells / physiology
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / physiology*
  • Jagged-1 Protein
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology*
  • Neural Crest / cytology*
  • Neural Crest / physiology*
  • Neural Inhibition / genetics
  • Neural Inhibition / physiology
  • Neurons / cytology
  • Neurons / physiology
  • Rats
  • Receptor, Notch1 / antagonists & inhibitors
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / physiology
  • Serrate-Jagged Proteins
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Solubility
  • Stem Cells / cytology*
  • Stem Cells / metabolism
  • Stem Cells / physiology*

Substances

  • Calcium-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jag1 protein, rat
  • Jagged-1 Protein
  • Membrane Proteins
  • Notch1 protein, rat
  • Receptor, Notch1
  • Serrate-Jagged Proteins