Histologic and transcriptional assessment of a mild SMA model
Histologic and transcriptional assessment of a mild SMA model
复制标题
DOI：
10.1179/016164107x159243
复制
发表时间：
2007-07-01
影响因子：
1.9
通讯作者：
MacKenzie, Alex E.
中科院分区：
文献类型：
--
作者：
Balabanian, Sylvia;Gendron, Nathalie H.;MacKenzie, Alex E.
脊髓性肌萎缩症（SMA）是由运动神经元存活（SMN）缺陷引起的，导致特定的运动神经元磨损。在SMA中观察到的运动神经元丢失的时间进程和分子病理生理学病因仍不清楚。Smn杂合子小鼠在6月龄时显示高达50%的运动神经元损耗，并用作人类轻度SMA的模型。为了确定SMA中细胞丢失率和运动神经元变性的分子事件，在Smn（+/-）小鼠和野生型同窝小鼠的脊髓中进行运动神经元计数和mRNA定量。令人惊讶的是，尽管运动神经元损失的慢性，亚临床性质，我们发现，大部分损失发生在5周龄。从5周龄Smn（+/-）小鼠脊髓中分离的RNA进行微阵列分析，揭示了参与RNA代谢、细胞凋亡和转录调控的基因的改变，包括编码钙结合蛋白的转录本的一般扰动。在不同时间点通过半定量RT-PCR和Western印迹分析进一步表征这些表达变化的子集。两者合计，这些结果表明，脊髓细胞呈现的第一个迹象的凋亡过程与响应的应力Smn耗尽。尽管SMA的性质非常温和，但获得了相对快速的神经元磨损的图片。此外，发生变化，这可能是反应性的，而不是导致细胞损失，涉及中央细胞功能以及钙调节蛋白。
Spinal muscular atrophy (SMA) is caused by survival of motor neuron ( SMN) deficiency, leading to specific motor neuron attrition. The time course and molecular pathophysiologic etiology of motor neuron loss observed in SMA remains obscure. Mice heterozygous for Smn show up to 50% motor neuron attrition by 6 months of age and are used as a model for mild SMA in humans. To determine both the rate of cellular loss and the molecular events underlying motor neuron degeneration in SMA, motor neuron counts and mRNA quantification were performed in spinal cords of Smn(+/-) mice and wild-type littermates. Surprisingly, despite the chronic, subclinical nature of motor neuron loss, we find that the bulk of the loss occurs by 5 weeks of age. RNA isolated from the spinal cords of 5 week-old Smn(+/-) mice subjected to microarray analysis reveal alterations in genes involved in RNA metabolism, apoptosis and transcriptional regulation including a general perturbation of transcripts coding for calcium binding proteins. A subset of these changes in expression was further characterized by semi-quantitative RT-PCR and Western blot analysis at various time points. Taken together, these results indicate that spinal cord cells present the first signs of the apoptotic process consistent with a response to the stress of Smn depletion. A picture of comparatively rapid neuronal attrition in spite of the very mild nature of SMA is obtained. Furthermore, changes occur, which may be reactive to and not causative of the cellular loss, involving central cellular functions as well as calcium modulating proteins.