Brain area-specific effect of TGF-β signaling on Wnt-dependent neural stem cell expansion
Brain area-specific effect of TGF-β signaling on Wnt-dependent neural stem cell expansion
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DOI：
10.1016/j.stem.2008.03.006
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发表时间：
2008-05-01
期刊：
影响因子：
23.9
通讯作者：
Sommer, Lukas
中科院分区：
文献类型：
--
作者：
Falk, Sven;Wurdak, Heiko;Sommer, Lukas
调节神经干细胞维持与分化之间的选择决定了发育中大脑的生长和大小。在这里，我们将 TGF-β 信号传导确定为控制这些过程的关键因素。在早期发育阶段，TGF-β信号活性位于靠近神经上皮的心室表面。在中脑中，但在前脑中，Tgfbr2 消融会导致 Wnt1/β-catenin 和 FGF8 的异位表达、Wnt 靶基因的激活，以及由于细胞周期长度缩短和细胞周期退出减少而导致神经上皮细胞增殖和水平扩张增加。与这种表型一致，突变型神经上皮干细胞的自我更新在 FGF 存在下得到增强，并且需要 Wnt 信号传导。此外，TGF-β信号激活可以抵消Wnt相关的中脑神经上皮细胞的增殖。因此，TGF-β信号传导通过拮抗经典Wnt信号传导和负向调节神经上皮干细胞的自我更新来控制特定大脑区域（背侧中脑）的大小。
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-incluced 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.