The Wnt/β-catenin pathway directs neuronal differentiation of cortical neural precursor cells
The Wnt/β-catenin pathway directs neuronal differentiation of cortical neural precursor cells
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DOI：
10.1242/dev.01165
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发表时间：
2004-06-01
期刊：
影响因子：
4.6
通讯作者：
Gotoh, Y
中科院分区：
文献类型：
--
作者：
Hirabayashi, Y;Itoh, Y;Gotoh, Y
神经前体细胞（neural precursor cells，NPC）具有自我更新和产生神经元和神经胶质谱系的能力。NPC在增殖和分化之间的命运决定了分化细胞的数量和大脑每个区域的大小。然而，调节神经元分化时间的信号仍然不清楚。在这里，我们表明，Wnt信号抑制小鼠皮质NPC的自我更新能力，并连续促进其神经元分化。在小鼠皮质NPC培养物中Wnt 7a或β-连环蛋白的稳定形式的过表达诱导神经元分化，即使在存在Fgf 2的情况下也是如此，Fgf 2是该系统中的自我更新促进因子。此外，阻断Wnt信号传导导致体外和发育中的小鼠新皮质中皮质NPC的神经元分化的抑制。此外，β-连环蛋白/TCF复合物似乎直接调节neurogenin 1的启动子，neurogenin 1是一种与皮质神经元分化有关的基因。重要的是，稳定的β-连环蛋白在早期发育阶段不诱导皮质NPC的神经元分化，这与先前的报道一致，表明Wnt在早期NPC中具有自我更新促进功能。这些发现可能揭示了Wnt信号在神经发育过程中更广泛和阶段特异性的生理作用。
Neural precursor cells (NPCs) have the ability to self-renew and to give rise to neuronal and glial lineages. The fate decision of NPCs between proliferation and differentiation determines the number of differentiated cells and the size of each region of the brain. However, the signals that regulate the timing of neuronal differentiation remain unclear. Here, we show that Wnt signaling inhibits the self-renewal capacity of mouse cortical NPCs, and instructively promotes their neuronal differentiation. Overexpression of Wnt7a or of a stabilized form of beta-catenin in mouse cortical NPC cultures induced neuronal differentiation even in the presence of Fgf2, a self-renewal-promoting factor in this system. Moreover, blockade of Wnt signaling led to inhibition of neuronal differentiation of cortical NPCs in vitro and in the developing mouse neocortex. Furthermore, the beta-catenin/TCF complex appears to directly regulate the promoter of neurogenin 1, a gene implicated in cortical neuronal differentiation. Importantly, stabilized beta-catenin did not induce neuronal differentiation of cortical NPCs at earlier developmental stages, consistent with previous reports indicating self-renewal-promoting functions of Wnts in early NPCs. These findings may reveal broader and stage-specific physiological roles of Wnt signaling during neural development.