The fragile X protein controls microtubule-associated protein 1B translation and microtubule stability in brain neuron development
The fragile X protein controls microtubule-associated protein 1B translation and microtubule stability in brain neuron development
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DOI：
10.1073/pnas.0404995101
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发表时间：
2004-10-19
影响因子：
11.1
通讯作者：
Feng, Y
中科院分区：
文献类型：
--
作者：
Lu, R;Wang, HP;Feng, Y
脆性X智力低下蛋白（FMRP）是一种选择性RNA结合蛋白，参与调节其mRNA配体的翻译。缺乏FMRP会导致脆性X综合征，这是遗传性智力低下的主要原因之一。在脆性X智力低下患者和Fmr1基因敲除（KO）小鼠中发现了延迟的树突棘成熟，表明FMRP在突触发育中的功能要求。然而，在脑发育过程中FMRP缺乏和神经元损伤之间的生物化学联系尚未确定。FMRP如何控制大脑中正常的突触发育仍然是一个谜。我们在这里报告说，发育编程FMRP表达抑制微管相关蛋白1B（MAP1B）的翻译，并需要在新生儿大脑发育的活跃突触发生过程中的MAP1B的加速下降。FMRP的缺乏导致在Fmr1（KC）脑中MAP1B翻译失调和MAP1B下降延迟。此外，异常升高的MAP1B蛋白表达导致Fmr1（KC）神经元中微管稳定性异常增加。总之，这些结果表明，FMRP在控制神经元发育过程中的细胞骨架组织中起着至关重要的作用，异常的微管动力学是脆性X智力低下发病机制的一个可能的潜在因素。
The fragile X mental retardation protein (FMRP) is a selective RNA-binding protein implicated in regulating translation of its mRNA ligands. The absence of FMRP results in fragile X syndrome, one of the leading causes of inherited mental retardation. Delayed dendritic spine maturation was found in fragile X mental retardation patients as well as in Fmr1 knockout (KO) mice, indicating the functional requirement of FMRP in synaptic development. However, the biochemical link between FMRP deficiency and the neuronal impairment during brain development has not been defined. How FMRP governs normal synapse development in the brain remains elusive. We report here that the developmentally programmed FMRP expression represses the translation of microtubule associated protein 1B (MAP1B) and is required for the accelerated decline of MAP1B during active synaptogenesis in neonatal brain development. The lack of FMRP results in misregulated MAP1B translation and delayed MAP1B decline in the Fmr1 KC) brain. Furthermore, the aberrantly elevated MAP1B protein expression leads to abnormally increased microtubule stability in Fmr1 KC) neurons. Together, these results indicate that FMRP plays critical roles in controlling cytoskeleton organization during neuronal development, and the abnormal microtubule dynamics is a conceivable underlying factor for the pathogenesis of fragile X mental retardation.