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Abstract：
The numerous neurons and glia that form the brain originate from tightly controlled growth and division of neural stem cells, regulated systemically by important known stem cell-extrinsic signals. However, the cell-intrinsic mechanisms that control the distinctive proliferation rates of individual neural stem cells are unknown. Here, we show that the size and division rates of Drosophila neural stem cells (neuroblasts) are controlled by the highly conserved RNA binding protein Imp (IGF2BP), via one of its top binding targets in the brain, myc mRNA. We show that Imp stabilises myc mRNA leading to increased Myc protein levels, larger neuroblasts, and faster division rates. Declining Imp levels throughout development limit myc mRNA stability to restrain neuroblast growth and division, and heterogeneous Imp expression correlates with myc mRNA stability between individual neuroblasts in the brain. We propose that Imp-dependent regulation of myc mRNA stability fine-tunes individual neural stem cell proliferation rates.
The brain is a highly complex organ made up of huge numbers of different cell types that connect up to form a precise network. All these different cell types are generated from the repeated division of a relatively small pool of cells called neural stem cells. The division of these cells needs to be carefully regulated so that the correct number and type of nerve cells are produced at the right time and place. But it remains unclear how the division rate of individual neural stem cells is controlled during development. Controlling these divisions requires the activity of countless genes to be tightly regulated over space and time. When a gene is active, it is copied via a process called transcription into a single-stranded molecule known as messenger RNA (or mRNA for short). This molecule provides the instructions needed to build the protein encoded within the gene. Proteins are the functional building blocks of all cells. The conventional way of controlling protein levels is to vary the number of mRNA molecules made by transcription. Now, Samuels et al. reveal a second mechanism of determining protein levels in the brain, through regulating the stability of mRNA after it is transcribed. Samuels et al. discovered that a key regulatory protein called Imp controls the growth and division of individual neural stem cells in the brains of developing fruit flies. The experiments showed that Imp binds to mRNA molecules that contain the code for a protein called Myc, which is known to drive cell growth and division in many different cell types. Both human Imp and Myc have been implicated in cancer. Using a technique that images single molecules of mRNA, Samuels et al. showed that the Imp protein in stem cells stabilises the mRNA molecule coding for Myc. This means that when more Imp is present, more Myc protein gets produced. Thus, the level of Imp in each individual neural stem cell fine-tunes the rate at which the cell grows and divides: the higher the level of Imp, the larger the stem cell and the faster it divides. These findings underscore how important post-transcriptional processes are for regulating gene activity in the developing brain. The methods used in this study to study mRNA molecules in single cells also provide new insights that could not be derived from the average measurements of many cells. Similar methods could also be applied to other developmental systems in the future.
The brain is a highly complex organ made up of huge numbers of different cell types that connect up to form a precise network. All these different cell types are generated from the repeated division of a relatively small pool of cells called neural stem cells. The division of these cells needs to be carefully regulated so that the correct number and type of nerve cells are produced at the right time and place. But it remains unclear how the division rate of individual neural stem cells is controlled during development. Controlling these divisions requires the activity of countless genes to be tightly regulated over space and time. When a gene is active, it is copied via a process called transcription into a single-stranded molecule known as messenger RNA (or mRNA for short). This molecule provides the instructions needed to build the protein encoded within the gene. Proteins are the functional building blocks of all cells. The conventional way of controlling protein levels is to vary the number of mRNA molecules made by transcription. Now, Samuels et al. reveal a second mechanism of determining protein levels in the brain, through regulating the stability of mRNA after it is transcribed. Samuels et al. discovered that a key regulatory protein called Imp controls the growth and division of individual neural stem cells in the brains of developing fruit flies. The experiments showed that Imp binds to mRNA molecules that contain the code for a protein called Myc, which is known to drive cell growth and division in many different cell types. Both human Imp and Myc have been implicated in cancer. Using a technique that images single molecules of mRNA, Samuels et al. showed that the Imp protein in stem cells stabilises the mRNA molecule coding for Myc. This means that when more Imp is present, more Myc protein gets produced. Thus, the level of Imp in each individual neural stem cell fine-tunes the rate at which the cell grows and divides: the higher the level of Imp, the larger the stem cell and the faster it divides. These findings underscore how important post-transcriptional processes are for regulating gene activity in the developing brain. The methods used in this study to study mRNA molecules in single cells also provide new insights that could not be derived from the average measurements of many cells. Similar methods could also be applied to other developmental systems in the future.
摘要：
形成大脑的众多神经元和神经胶质起源于严格控制的神经干细胞的生长和分裂，由重要的已知干细胞外在信号系统调节。然而,控制单个神经干细胞独特增殖速率的细胞内在机制尚不清楚.这里,我们表明果蝇神经干细胞（神经母细胞）的大小和分裂率是由高度保守的RNA结合蛋白Imp（IGF2BP）控制的，通过它在大脑中的一个主要结合目标，mycmRNA。我们表明Imp稳定mycmRNA，导致Myc蛋白水平增加，更大的神经母细胞，和更快的分裂率。整个发育过程中Imp水平的下降限制了mycmRNA的稳定性，从而抑制成神经细胞的生长和分裂，和异质Imp表达与脑中单个成神经细胞之间的mycmRNA稳定性相关。我们认为Imp依赖性调节mycmRNA稳定性可以微调单个神经干细胞的增殖率。
大脑是一个高度复杂的器官，由大量不同类型的细胞组成，这些细胞连接形成精确的网络。所有这些不同的细胞类型都是由称为神经干细胞的相对较小的细胞池的重复分裂产生的。需要仔细调节这些细胞的分裂，以便在正确的时间和地点产生正确数量和类型的神经细胞。但目前尚不清楚单个神经干细胞的分裂率在发育过程中是如何控制的。控制这些分裂需要无数基因的活性在空间和时间上受到严格调节。当一个基因活跃时，它通过称为转录的过程被复制到称为信使RNA（或简称mRNA）的单链分子中。该分子提供了构建基因内编码的蛋白质所需的指令。蛋白质是所有细胞的功能构件。控制蛋白质水平的常规方法是改变通过转录产生的mRNA分子的数量。现在,Samuels等人。揭示了决定大脑蛋白质水平的第二种机制，通过调节mRNA转录后的稳定性。Samuels等人。发现一种称为Imp的关键调节蛋白控制发育果蝇大脑中单个神经干细胞的生长和分裂。实验表明，Imp与包含Myc蛋白质密码的mRNA分子结合，已知在许多不同的细胞类型中驱动细胞生长和分裂。人类Imp和Myc都与癌症有关。使用一种成像单分子mRNA的技术，Samuels等人。显示干细胞中的Imp蛋白稳定了编码Myc的mRNA分子。这意味着当更多的Imp存在时，产生更多的Myc蛋白。因此，每个神经干细胞中的Imp水平会微调细胞生长和分裂的速率：Imp水平越高，干细胞越大，分裂越快。这些发现强调了转录后过程对于调节发育中的大脑中的基因活性的重要性。本研究中用于研究单细胞中mRNA分子的方法也提供了新的见解，这些见解无法从许多细胞的平均测量中得出。类似的方法将来也可以应用于其他开发系统。
大脑是一个高度复杂的器官，由大量不同类型的细胞组成，这些细胞连接形成精确的网络。所有这些不同的细胞类型都是由称为神经干细胞的相对较小的细胞池的重复分裂产生的。需要仔细调节这些细胞的分裂，以便在正确的时间和地点产生正确数量和类型的神经细胞。但目前尚不清楚单个神经干细胞的分裂率在发育过程中是如何控制的。控制这些分裂需要无数基因的活性在空间和时间上受到严格调节。当一个基因活跃时，它通过称为转录的过程被复制到称为信使RNA（或简称mRNA）的单链分子中。该分子提供了构建基因内编码的蛋白质所需的指令。蛋白质是所有细胞的功能构件。控制蛋白质水平的常规方法是改变通过转录产生的mRNA分子的数量。现在,Samuels等人。揭示了决定大脑蛋白质水平的第二种机制，通过调节mRNA转录后的稳定性。Samuels等人。发现一种称为Imp的关键调节蛋白控制发育果蝇大脑中单个神经干细胞的生长和分裂。实验表明，Imp与包含Myc蛋白质密码的mRNA分子结合，已知在许多不同的细胞类型中驱动细胞生长和分裂。人类Imp和Myc都与癌症有关。使用一种成像单分子mRNA的技术，Samuels等人。显示干细胞中的Imp蛋白稳定了编码Myc的mRNA分子。这意味着当更多的Imp存在时，产生更多的Myc蛋白。因此，每个神经干细胞中的Imp水平会微调细胞生长和分裂的速率：Imp水平越高，干细胞越大，分裂越快。这些发现强调了转录后过程对于调节发育中的大脑中的基因活性的重要性。本研究中用于研究单细胞中mRNA分子的方法也提供了新的见解，这些见解无法从许多细胞的平均测量中得出。类似的方法将来也可以应用于其他开发系统。
