TY - JOUR
T1 - Brain area-specific effect of TGF-β signaling on Wnt-dependent neural stem cell expansion
AU - Falk, Sven
AU - Wurdak, Heiko
AU - Ittner, Lars M.
AU - Ille, Fabian
AU - Sumara, Grzegorz
AU - Schmid, Marie Theres
AU - Draganova, Kalina
AU - Lang, Karl S.
AU - Paratore, Christian
AU - Leveen, Per
AU - Suter, Ueli
AU - Karlsson, Stefan
AU - Born, Walter
AU - Ricci, Romeo
AU - Götz, Magdalena
AU - Sommer, Lukas
PY - 2008/5/8
Y1 - 2008/5/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=42649120343&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2008.03.006
DO - 10.1016/j.stem.2008.03.006
M3 - Article
C2 - 18462697
AN - SCOPUS:42649120343
SN - 1934-5909
VL - 2
SP - 472
EP - 483
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 5
ER -