Brain area-specific effect of TGF-beta signaling on Wnt-dependent neural stem cell expansion.
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.
Falk
Sven
S
Institute of Cell Biology, ETH-Hönggerberg, CH-8093 Zurich, Switzerland.
Wurdak
Heiko
H
Ittner
Lars M
LM
Ille
Fabian
F
Sumara
Grzegorz
G
Schmid
Marie-Theres
MT
Draganova
Kalina
K
Lang
Karl S
KS
Paratore
Christian
C
Leveen
Per
P
Suter
Ueli
U
Karlsson
Stefan
S
Born
Walter
W
Ricci
Romeo
R
Götz
Magdalena
M
Sommer
Lukas
L
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000502:physiology; D002454:Cell Differentiation; D006801:Humans; D008636:Mesencephalon / Q000166:cytology* / Q000196:embryology / Q000502:physiology*; D051379:Mice; D046569:Neuroepithelial Cells / Q000166:cytology / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology; D009928:Organ Specificity; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D051155:Wnt1 Protein / Q000502:physiology*
D018797:Cell Cycle Proteins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C495247:WNT1 protein, human; D051155:Wnt1 Protein; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II