Temporal patterning of neural progenitors to generate neural diversity

神经多样性的产生是发育神经生物学中的一个关键问题。研究项目： 脊椎动物和无脊椎动物模式生物都表明，神经前体是 以时间模式以定义的顺序生成不同的神经类型，并且该顺序可以是 在体外培养的祖细胞中重述，暗示有内在的时钟。然而， 其分子机制尚不清楚。延髓果蝇是一种独特的系统 这个问题，因为在连续的时间阶段的神经前体(神经母细胞)可以 在一张图片中被视觉化。最近，一种新的转录因子(TTF)的时间级联， 同胸(HTH)、无眼(EY)、马虎配对1和2(SLP)、双毛(D)和无尾(TLL)、 发现随着年龄的增长，这些基因在髓质神经母细胞中顺序表达。每个基因都服务于 作为相应时间阶段的‘主调节器’，控制神经元的身份。这个 不同时间阶段之间的时间转换需要一个TTF激活下一个， 并压制前一个。下一个TTF表达的激活是一个渐进的过程 国家统计局中连续的信托基金之间有很大的重叠。然而，有一个 神经元后代从表达一种TTF到表达下一种TTF的急剧过渡，没有重叠。 这对于在连续的时间阶段产生不同的神经同一性至关重要。这项建议 正在解决神经前体细胞发育时序控制的两个基本问题： 1)神经前体细胞中下一个TTF的逐渐打开是如何“转化”成尖锐的 子代的时间转换？2)时间转换是如何被精确调控的 控制每个阶段出生的神经元的数量？初步数据暗示了一种假设 其中，下一个TTF的表达在NBS中由其在 细胞周期依赖的方式，但下一个TTF基因的转录在后代中受到抑制 在其从Nb继承的蛋白质达到特定阈值以抵消抑制之前， 然后，神经元后代发生转变。此外，初步数据显示， 当NBS在细胞中被阻止时，时间基因级联中的进展不会发生 循环，这表明时间级数不依赖于绝对时间，而是 细胞周期进程。总之，依赖于细胞周期的振荡可以用作时钟， 而递进的、不可逆的时间基因级联可以作为累积的 每个细胞周期留下标记的时间记录，提供了一种机制来控制 在每个时间阶段出生的神经元的数量。

Generation of neural diversity is a key question in developmental neurobiology. Studies in both vertebrates and invertebrate model organisms have shown that neural progenitors are temporally patterned to generate different neural types in a defined order, and this order can be recapitulated in progenitors cultured in vitro, suggesting an internal clock. However, the molecule mechanism is not yet clear. The Drosophila medulla is a unique system to address this question, because the neural progenitors (neuroblasts) at consecutive temporal stages can be visualized in one image. Recently a novel Temporal cascade of Transcription Factors (TTFs), Homothorax (Hth), Eyeless (Ey), Sloppy paired 1 and 2 (Slp), Dichaete (D) and Tailless (Tll), were found to be expressed sequentially in medulla neuroblasts as they age. Each gene serves as the ‘master regulator” of the corresponding temporal stage, and control neuron identity. The temporal transitions between different temporal stages require that one TTF activates the next, and represses the previous one. The activation of the next TTF’s expression is a gradual process, and there is a large overlap between successive TTFs in NBs. However, there is a sharp transition in the neuronal progeny from expressing one TTF to the next with no overlap. This is critical to generate distinct neural identities in successive temporal stages. This proposal is addressing two fundamental questions of developmental timing control in neural progenitors: 1) How is the gradual turning on the next TTF in neural progenitors “translated” into a sharp temporal transition in the progeny? 2) How is the temporal transition regulated to precisely control the number of neurons born at each stage? The preliminary data suggest a hypothesis in which the expression of the next TTF is activated gradually in NBs by its preceding TTF in a cell-cycle dependent way, but the transcription of the next TTF gene is repressed in the progeny before its protein inherited from the NB reaches a certain threshold to counteract the repression, and then the transition in the neuronal progeny occurs. Further, preliminary data show that the progression in the temporal gene cascade does not happen when NBs are arrested in the cell cycle, suggesting that the temporal progression is not dependent on the absolute time, but the cell-cycle progression. In summary cell cycle dependent oscillations could serve as the clock, and the progressive and irreversible temporal gene cascade could serve as the accumulative record of time with each cell cycle leaving its mark, providing a mechanism to control the number of neurons born at each temporal stage.