西亚试剂：Brain Area-Specific Effect of TGF-β Signaling on Wnt-Depend

Brain Area-Specific Effect of TGF-β Signaling on Wnt-Dependent Neural Stem Cell Expansion
Sven Falk,1,9,10 Heiko Wurdak,1,9,11 Lars M. Ittner,2,12 Fabian Ille,1 Grzegorz Sumara,1 Marie-Theres Schmid,3 Kalina Draganova,10 Karl S. Lang,6 Christian Paratore,1 Per Leveen,7,8 Ueli Suter,1 Stefan Karlsson,7,8 Walter Born,2 Romeo Ricci,1 Magdalena Götz,3,4,5 and Lukas Sommer1,10,

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
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.

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