Fragile X mental retardation protein regulates new neuron differentiation in the adult olfactory bulb.
Fragile X mental retardation protein regulates new neuron differentiation in the adult olfactory bulb.
复制标题
DOI：
10.1523/jneurosci.5514-10.2011
复制
发表时间：
2011-02-09
期刊：
影响因子：
--
通讯作者：
Caillé I
中科院分区：
文献类型：
--
作者：
Scotto-Lomassese S;Nissant A;Mota T;Néant-Féry M;Oostra BA;Greer CA;Lledo PM;Trembleau A;Caillé I
脆性X智力迟钝蛋白（FMRP）是一种rna结合蛋白，对神经元mRNA代谢的多个方面至关重要。它的缺失会导致脆性X染色体综合征，这是最普遍的智力迟钝的遗传形式。这种疾病的解剖学标志，也存在于Fmr1敲除（KO）小鼠中，是大量看起来不成熟的延长树突棘。我们利用众所周知的小鼠嗅球（OB）中成体颗粒细胞（GCs）的连续生成来分析Fmrp缺失对GCs分化的影响。Fmr1 KO小鼠的GCs形态学分析显示脊柱密度增加，但脊柱长度没有变化。我们开发了一种RNA干扰策略，在野生型OB网络中细胞自主突变Fmr1。突变的GCs显示脊柱密度和脊柱长度增加。通过免疫组织化学、电子显微镜和电生理学对脊髓的详细分析令人惊讶地表明，尽管存在这些异常，脊髓仍接受正常的谷氨酸能突触，因此突变的成年神经元突触整合到OB电路中。对脊柱缺损的时间过程分析表明，Fmrp细胞可自主下调脊柱生成的水平和速率，并限制其过度生长。最后，我们报道Fmrp在标准条件下不调节树突发生，但对于活性依赖性树突重塑是必要的。总的来说，我们在成人神经发生的背景下对Fmrp的研究使我们能够对Fmrp在神经元分化中的作用进行精确的解剖，并强调其在脊柱发生和树突发生中的多性参与。
The fragile X mental retardation protein (FMRP) is an RNA-binding protein essential for multiple aspects of neuronal mRNA metabolism. Its absence leads to the fragile X syndrome, the most prevalent genetic form of mental retardation. The anatomical landmark of the disease, also present in the Fmr1 knock-out (KO) mice, is the hyperabundance of immature-looking lengthened dendritic spines. We used the well known continuous production of adult-born granule cells (GCs) in the mouse olfactory bulb (OB) to analyze the consequences of Fmrp loss on the differentiation of GCs. Morphological analysis of GCs in the Fmr1 KO mice showed an increase in spine density without a change in spine length. We developed an RNA interference strategy to cell-autonomously mutate Fmr1 in a wild-type OB network. Mutated GCs displayed an increase in spine density and spine length. Detailed analysis of the spines through immunohistochemistry, electron microscopy, and electrophysiology surprisingly showed that, despite these abnormalities, spines receive normal glutamatergic synapses, and thus that mutated adult-born neurons are synaptically integrated into the OB circuitry. Time-course analysis of the spine defects showed that Fmrp cell-autonomously downregulates the level and rate of spine production and limits their overgrowth. Finally, we report that Fmrp does not regulate dendritogenesis in standard conditions but is necessary for activity-dependent dendritic remodeling. Overall, our study of Fmrp in the context of adult neurogenesis has enabled us to carry out a precise dissection of the role of Fmrp in neuronal differentiation and underscores its pleiotropic involvement in both spinogenesis and dendritogenesis.