Fragile X protein controls neural stem cell proliferation in the Drosophila brain
Fragile X protein controls neural stem cell proliferation in the Drosophila brain
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DOI：
10.1093/hmg/ddq213
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发表时间：
2010-08-01
影响因子：
3.5
通讯作者：
Zarnescu, Daniela C.
中科院分区：
文献类型：
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作者：
Callan, Matthew A.;Cabernard, Clemens;Zarnescu, Daniela C.
脆性X综合征(FXS)是最常见的遗传性智力低下，由脆性X蛋白(FMRP)功能丧失引起，FMRP是一种RNA结合蛋白，被认为通过控制特定mRNAs的定位和翻译来调节突触的可塑性。我们最近证明，FMRP是控制果蝇生殖系增殖所必需的。为了确定FMRP是否也是脑发育过程中增殖所必需的，我们研究了dFmr1脑中细胞周期标记物的分布，并与野生型进行了比较。我们的结果表明，dFmr1的缺失导致脑内有丝分裂神经母细胞(NB)数量和BrdU掺入显著增加，这与FMRP在神经发生过程中控制增殖的观点一致。发育研究表明，Fmrp还抑制早期幼虫脑内成神经细胞从静止状态退出，Cyclin E的错误表达表明。实时成像实验表明，到3龄幼虫阶段，细胞周期长度不受影响，尽管与野生型相比，dFmr1脑中发现更多的细胞位于S和G2/M期。为了确定FMRP在神经母细胞分裂和分化中的作用，我们在发育中的幼虫脑中使用了嵌合分析和可抑制标记(MARCM)方法，发现单个dFmr1NB产生的神经元明显多于对照组。我们的结果表明，FMRP在大脑发育过程中是必需的，以控制NB的退出和增殖能力以及神经元的产生，这可能为了解FXS的自闭症成分提供了线索。
Fragile X syndrome (FXS) is the most common form of inherited mental retardation and is caused by the loss of function for Fragile X protein (FMRP), an RNA-binding protein thought to regulate synaptic plasticity by controlling the localization and translation of specific mRNAs. We have recently shown that FMRP is required to control the proliferation of the germline in Drosophila. To determine whether FMRP is also required for proliferation during brain development, we examined the distribution of cell cycle markers in dFmr1 brains compared with wild-type throughout larval development. Our results indicate that the loss of dFmr1 leads to a significant increase in the number of mitotic neuroblasts (NB) and BrdU incorporation in the brain, consistent with the notion that FMRP controls proliferation during neurogenesis. Developmental studies suggest that FMRP also inhibits neuroblast exit from quiescence in early larval brains, as indicated by misexpression of Cyclin E. Live imaging experiments indicate that by the third instar larval stage, the length of the cell cycle is unaffected, although more cells are found in S and G2/M in dFmr1 brains compared with wildtype. To determine the role of FMRP in neuroblast division and differentiation, we used Mosaic Analysis with a Repressible Marker (MARCM) approaches in the developing larval brain and found that single dFmr1 NB generate significantly more neurons than controls. Our results demonstrate that FMRP is required during brain development to control the exit from quiescence and proliferative capacity of NB as well as neuron production, which may provide insights into the autistic component of FXS.