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

Sven Falk, Heiko Wurdak, Lars M. Ittner, Fabian Ille, Grzegorz Sumara, Marie Theres Schmid, Kalina Draganova, Karl S. Lang, Christian Paratore, Per Leveen, Ueli Suter, Stefan Karlsson, Walter Born, Romeo Ricci, Magdalena Götz, Lukas Sommer*

*Corresponding author for this work

Research output: Contribution to journalArticle

97 Citations (Scopus)

Abstract

Regulating the choice between neural stem cell maintenance versus differentiation determines growth and size of the developing brain. Here we identify TGF-β signaling as a crucial factor controlling these processes. At early developmental stages, TGF-β 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/β-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-β signal activation counteracts Wnt-induced proliferation of midbrain neuroepithelial cells. Thus, TGF-β 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.

Original languageEnglish
Pages (from-to)472-483
Number of pages12
JournalCell Stem Cell
Volume2
Issue number5
DOIs
Publication statusPublished - 8 May 2008
Externally publishedYes

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