Copyright © 2008 Cell Press. All rights reserved.
Cell Stem Cell, Vol 2, 472-483, 08 May 2008
Article
Brain Area-Specific Effect of TGF-β Signaling on Wnt-Dependent Neural Stem Cell Expansion
1 Institute of Cell Biology, ETH-Hönggerberg, CH-8093 Zurich, Switzerland
2 Orthopedic University Hospital Balgrist, CH-8008 Zurich, Switzerland
3 Institute of Stem Cell Research, HelmholtzZentrum Munchen, National Research, Center for Environmental Health, D-85764 Neuherberg/Munich, Germany
4 Physiological Genomics, University of Munich, D-80633 Munich, Germany
5 Center for Integrated Protein Science Munich, D-80633 Munich, Germany
6 Institute of Experimental Immunology, University Hospital Zurich, CH-8091 Zurich, Switzerland
7 Department of Molecular Medicine and Gene Therapy, Lund University, S-22184 Lund, Sweden
8 Department of Cell and Molecular Biology, Lund University, S-22184 Lund, Sweden
∗Corresponding author
Lukas Sommer
lukas.sommer@anatom.uzh.ch
Summary
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.
Footnotes
9 These authors contributed equally to this work.
10 Present address: Institute of Anatomy, University of Zurich, CH-8057 Zurich, Switzerland.
11 Present address: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
12 Present address: Alzheimer's and Parkinson's Disease Laboratories, Brain and Mind Research Institute, University of Sydney, NSW-2050 Sydney, Australia.
