Brain area-specific effect of TGF-beta signaling on Wnt-dependent neural stem cell expansion

Cell Stem Cell. 2008 May 8;2(5):472-83. doi: 10.1016/j.stem.2008.03.006.

Abstract

Regulating the choice between neural stem cell maintenance versus differentiation determines growth and size of the developing brain. Here we identify TGF-beta signaling as a crucial factor controlling these processes. At early developmental stages, TGF-beta signal activity is localized close to the ventricular surface of the neuroepithelium. In the midbrain, but not in the forebrain, Tgfbr2 ablation results in ectopic expression of Wnt1/beta-catenin and FGF8, activation of Wnt target genes, and increased proliferation and horizontal expansion of neuroepithelial cells due to shortened cell-cycle length and decreased cell-cycle exit. Consistent with this phenotype, self-renewal of mutant neuroepithelial stem cells is enhanced in the presence of FGF and requires Wnt signaling. Moreover, TGF-beta signal activation counteracts Wnt-induced proliferation of midbrain neuroepithelial cells. Thus, TGF-beta signaling controls the size of a specific brain area, the dorsal midbrain, by antagonizing canonical Wnt signaling and negatively regulating self-renewal of neuroepithelial stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle / physiology
  • Cell Cycle Proteins / physiology
  • Cell Differentiation*
  • Humans
  • Mesencephalon / cytology*
  • Mesencephalon / embryology
  • Mesencephalon / physiology*
  • Mice
  • Neuroepithelial Cells / cytology
  • Neuroepithelial Cells / physiology
  • Neurons / cytology
  • Neurons / physiology
  • Organ Specificity
  • Protein-Serine-Threonine Kinases / metabolism
  • Rats
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction*
  • Stem Cells / cytology*
  • Stem Cells / physiology*
  • Transforming Growth Factor beta / physiology*
  • Wnt1 Protein / physiology*

Substances

  • Cell Cycle Proteins
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • WNT1 protein, human
  • Wnt1 Protein
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II