Hedgehog signaling acts with the temporal cascade to promote neuroblast cell cycle exit.
Hedgehog signaling acts with the temporal cascade to promote neuroblast cell cycle exit.
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DOI：
10.1371/journal.pbio.1001494
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发表时间：
2013
期刊：
影响因子：
9.8
通讯作者：
Cai Y
中科院分区：
文献类型：
--
作者：
Chai PC;Liu Z;Chia W;Cai Y
在果蝇神经系统的发育过程中，发育调节的Hedgehog通路与一系列时间转录因子一起，安排了神经发生的结束。在果蝇胚后成神经细胞中，转录因子级联（也称为时间序列）的基因表达程序的转变与不对称分裂机制一起作用，产生具有不同身份的不同神经元，并调节成神经细胞增殖的结束。然而，这种“时间序列”在发育过程中如何发挥作用的潜在机制仍不清楚。在这里，我们表明，Hh信号在胚后大脑的时间调节;过量（早期发病）Hh信号导致过早的神经母细胞细胞周期退出和增殖不足，而Hh信号的损失导致延迟的细胞周期退出和过度增殖。此外，Hh通路的功能下游的蓖麻，但上游的Grainyhead，时间序列的两个组成部分，调度成神经细胞的细胞周期退出。有趣的是，hh很可能是Castor的目标。因此，Hh信号提供了时间序列和不对称分裂机制之间的联系，在调度神经发生的结束。在几乎所有的后生动物中，神经元都是由一组神经干细胞/祖细胞以精确的时间方式产生的，这对于产生功能性神经系统非常重要。在果蝇中，这种“定时”机制主要由称为神经母细胞的神经干细胞中转录因子的顺序切换控制，因此神经元的命运与其出生顺序相关。这些时间因素也协调终止成神经细胞分裂对神经发生结束。在这项研究中，我们表明，刺猬（Hh）信号也调节分裂率的神经母细胞在其增殖阶段在幼虫阶段，以及停止增殖在早期蛹阶段。过量的Hh信号传导导致神经母细胞的细胞周期提前退出和神经发生的提前终止，而Hh信号传导的缺失导致神经母细胞的增殖延长超过其生理窗口。我们还发现，Hh信号与时间转录因子协同作用，并且本身受这些因子的调节。我们假设这种相互作用模式（时间转录因子与发育调节信号，如Hh）在神经发生过程中可以广泛保存在其他生物体。
During the development of the Drosophila nervous system, the developmentally regulated Hedgehog pathway, together with a series of temporal transcription factors, schedules the end of neurogenesis. In Drosophila postembryonic neuroblasts, transition in gene expression programs of a cascade of transcription factors (also known as the temporal series) acts together with the asymmetric division machinery to generate diverse neurons with distinct identities and regulate the end of neuroblast proliferation. However, the underlying mechanism of how this “temporal series” acts during development remains unclear. Here, we show that Hh signaling in the postembryonic brain is temporally regulated; excess (earlier onset of) Hh signaling causes premature neuroblast cell cycle exit and under-proliferation, whereas loss of Hh signaling causes delayed cell cycle exit and excess proliferation. Moreover, the Hh pathway functions downstream of Castor but upstream of Grainyhead, two components of the temporal series, to schedule neuroblast cell cycle exit. Interestingly, hh is likely a target of Castor. Hence, Hh signaling provides a link between the temporal series and the asymmetric division machinery in scheduling the end of neurogenesis. In almost all metazoans, neurons are produced by a group of neural stem cells/progenitors in a precise temporal manner, which is important for generating a functional nervous system. In Drosophila, this “timing” mechanism is mainly governed by the sequential switching of transcription factors in neural stem cells called neuroblasts, such that neuronal fate is associated with its birth order. These temporal factors also coordinate the termination of neuroblast division towards the end of neurogenesis. In this study, we show that Hedgehog (Hh) signaling also regulates the division rate of neuroblasts during their proliferative phase at larval stage, as well as the cessation of proliferation at early pupal stage. Excessive Hh signaling causes premature neuroblast cell cycle exit and early termination of neurogenesis, while loss of Hh signaling results in prolonged proliferation of neuroblasts beyond its physiological window. We also find that Hh signaling acts in concert with the temporal transcription factors, and is itself regulated by these factors. We hypothesize that this mode of interaction (temporal transcription factors with developmentally regulated signals like Hh) during neurogenesis could be widely conserved in other organisms.
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