title: Brain area-specific effect of TGF-beta signaling on Wnt-dependent neural stem cell expansion.
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.
authors.affiliation: Institute of Cell Biology, ETH-Hönggerberg, CH-8093 Zurich, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Falk
authors.forename: Heiko
authors.initials: H
authors.lastname: Wurdak
authors.forename: Lars M
authors.initials: LM
authors.lastname: Ittner
authors.forename: Fabian
authors.initials: F
authors.lastname: Ille
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Sumara
authors.forename: Marie-Theres
authors.initials: MT
authors.lastname: Schmid
authors.forename: Kalina
authors.initials: K
authors.lastname: Draganova
authors.forename: Karl S
authors.initials: KS
authors.lastname: Lang
authors.forename: Christian
authors.initials: C
authors.lastname: Paratore
authors.forename: Per
authors.initials: P
authors.lastname: Leveen
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
authors.forename: Stefan
authors.initials: S
authors.lastname: Karlsson
authors.forename: Walter
authors.initials: W
authors.lastname: Born
authors.forename: Romeo
authors.initials: R
authors.lastname: Ricci
authors.forename: Magdalena
authors.initials: M
authors.lastname: Götz
authors.forename: Lukas
authors.initials: L
authors.lastname: Sommer
mesh_terms: 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*
chemical_list: 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