Murine hippocampal neurons expressing Fmr1 gene premutations show early developmental deficits and late degeneration
Murine hippocampal neurons expressing Fmr1 gene premutations show early developmental deficits and late degeneration
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DOI：
10.1093/hmg/ddp479
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发表时间：
2010-01-01
影响因子：
3.5
通讯作者：
Pessah, Isaac N.
中科院分区：
文献类型：
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作者：
Chen, Yucui;Tassone, Flora;Pessah, Isaac N.
脆性X智力低下1（FMR 1）基因内的前突变CGG重复扩增（55-200个CGG重复; preCGG）引起神经退行性疾病、脆性X相关震颤/共济失调综合征（FXTAS）、原发性卵巢功能不全和神经发育问题。Map 2B免疫荧光的形态学分析表明，与野生型（WT）同窝出生的小鼠相比，在体外培养的具有前CGG重复序列的杂合雌性小鼠的神经元在7至21天之间显示较短的树突长度和较少的分支。虽然突触蛋白和鬼笔环肽点的数量与WT没有差异，但前CGG神经元具有更大的点。前CGG神经元显示出较低的活力，并在成熟时表达升高的应激蛋白。前CGG神经元具有内在不同的生长模式，树突的复杂性和突触结构可辨别早期的神经元轨迹成熟，并可能反映了细胞基础的发展组成部分的频谱的临床参与的携带者的前突变等位基因。preCGG神经元活力降低与FXTAS相关的mRNA毒性和神经退行性变一致。
Premutation CGG repeat expansions (55-200 CGG repeats; preCGG) within the fragile X mental retardation 1 (FMR1) gene give rise to the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), primary ovarian insufficiency and neurodevelopmental problems. Morphometric analysis of Map2B immunofluorescence reveals that neurons cultured from heterozygous female mice with preCGG repeats in defined medium display shorter dendritic lengths and fewer branches between 7 and 21 days in vitro compared with wild-type (WT) littermates. Although the numbers of synapsin and phalloidin puncta do not differ from WT, preCGG neurons possess larger puncta. PreCGG neurons display lower viability, and express elevated stress protein as they mature. PreCGG neurons have inherently different patterns of growth, dendritic complexity and synaptic architecture discernable early in the neuronal trajectory to maturation, and may reflect a cellular basis for the developmental component of the spectrum of clinical involvement in carriers of premutation alleles. The reduced viability of preCGG neurons is consistent with the mRNA toxicity and neurodegeneration associated with FXTAS.