Tgfβ Signaling Regulates Temporal Neurogenesis and Potency of Neural Stem Cells in the CNS
Tgfβ Signaling Regulates Temporal Neurogenesis and Potency of Neural Stem Cells in the CNS
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DOI：
10.1016/j.neuron.2014.10.033
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发表时间：
2014-12-03
期刊：
影响因子：
16.2
通讯作者：
Ericson, Johan
中科院分区：
文献类型：
--
作者：
Dias, Jose M.;Alekseenko, Zhanna;Ericson, Johan
在脊椎动物的大脑发育中，神经元的顺序规范和与老化的神经前体细胞相关的渐进性潜能丧失是如何被调控的，目前还知之甚少。通过研究后脑的时间分化谱系，我们在这里确定转化生长因子β是一个开关信号，执行神经发生早期和晚期之间的转换，并同时限制祖细胞的潜能。年轻的祖细胞具有产生晚出生神经元的先天能力，但晚分化计划的实施需要抑制通过Shh信号下游的转化生长因子β的时间性编程激活而获得的早期同一性基因。出乎意料的是，我们发现，顺序发生的命运转换决定是时间上的耦合，转化生长因子β信号的启动似乎因此影响了时间谱系的整体寿命。我们的研究确立了转化生长因子β作为神经干细胞的时间特性和潜能的调节因子，并为在干细胞工程中应用转化生长因子β来调节神经元的时间特性提供了概念证据。
How the sequential specification of neurons and progressive loss of potency associated with aging neural progenitors are regulated in vertebrate brain development is poorly understood. By examining a temporal differentiation lineage in the hindbrain, we here identify Tgf beta as a switch signal that executes the transition between early and late phases of neurogenesis and concurrently constrains progenitor potency. Young progenitors have inherent competence to produce late-born neurons, but implementation of late-differentiation programs requires suppression of early identity genes achieved through temporally programmed activation of Tgf beta downstream of Shh signaling. Unexpectedly, we find that sequentially occurring fate-switch decisions are temporally coupled, and onset of Tgf beta signaling appears thereby to impact on the overall lifespan of the temporal lineage. Our study establishes Tgf beta as a regulator of temporal identity and potency of neural stem cells, and provides proof of concept that Tgf beta can be applied to modulate temporal specification of neurons in stem cell engineering.