Human Molecular Genetics and Physiology Program, Stanley Manne Children's Research Institute at Ann & Robert H. Lurie Children's Hospital, Chicago, IL, USA; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Human Molecular Genetics and Physiology Program, Stanley Manne Children's Research Institute at Ann & Robert H. Lurie Children's Hospital, Chicago, IL, USA.
Exp Neurol. 2021 Mar;337:113587. doi: 10.1016/j.expneurol.2020.113587. Epub 2020 Dec 28.
Spinal muscular atrophy (SMA) is a pediatric neuromuscular disease caused by genetic deficiency of the survival motor neuron (SMN) protein. Pathological hallmarks of SMA are spinal motor neuron loss and skeletal muscle atrophy. The molecular mechanisms that elicit and drive preferential motor neuron degeneration and death in SMA remain unclear. Transcriptomic studies consistently report p53 pathway activation in motor neurons and spinal cord tissue of SMA mice. Recent work has identified p53 as an inducer of spinal motor neuron loss in severe Δ7 SMA mice. Additionally, the cyclin-dependent kinase inhibitor P21 (Cdkn1a), an inducer of cell cycle arrest and mediator of skeletal muscle atrophy, is consistently increased in motor neurons, spinal cords, and other tissues of various SMA models. p21 is a p53 transcriptional target but can be independently induced by cellular stressors. To ascertain whether p53 and p21 signaling pathways mediate spinal motor neuron death in milder SMA mice, and how they affect the overall SMA phenotype, we introduced Trp53 and P21 null alleles onto the Smn background. We found that p53 and p21 depletion did not modulate the timing or degree of Smn motor neuron loss as evaluated using electrophysiological and immunohistochemical methods. Moreover, we determined that Trp53 and P21 knockout differentially affected Smn mouse lifespan: p53 ablation impaired survival while p21 ablation extended survival through Smn-independent mechanisms. These results demonstrate that p53 and p21 are not primary drivers of spinal motor neuron death in Smn mice, a milder SMA mouse model, as motor neuron loss is not alleviated by their ablation.
脊髓性肌萎缩症（SMA）是一种儿科神经肌肉疾病，由生存运动神经元（SMN）蛋白的遗传缺陷引起。SMA 的病理特征是脊髓运动神经元丧失和骨骼肌萎缩。引发和驱动 SMA 中运动神经元优先退化和死亡的分子机制仍不清楚。转录组学研究一致报告在 SMA 小鼠的运动神经元和脊髓组织中 p53 通路的激活。最近的工作已经确定 p53 是严重 Δ7 SMA 小鼠脊髓运动神经元丧失的诱导剂。此外，细胞周期蛋白依赖性激酶抑制剂 P21（Cdkn1a），一种细胞周期停滞的诱导剂和骨骼肌萎缩的介质，在各种 SMA 模型的运动神经元、脊髓和其他组织中持续增加。p21 是 p53 的转录靶标，但可以被细胞应激物独立诱导。为了确定 p53 和 p21 信号通路是否介导轻度 SMA 小鼠中的脊髓运动神经元死亡，以及它们如何影响 SMA 的整体表型，我们在 Smn 背景下引入了 Trp53 和 P21 缺失等位基因。我们发现，p53 和 p21 的缺失并没有通过电生理学和免疫组织化学方法评估 Smn 运动神经元丢失的时间或程度。此外，我们确定 Trp53 和 P21 敲除对 Smn 小鼠的寿命有不同的影响：p53 缺失会损害生存，而 p21 缺失通过 Smn 独立机制延长生存。这些结果表明，p53 和 p21 不是 Smn 小鼠，即轻度 SMA 小鼠模型中脊髓运动神经元死亡的主要驱动因素，因为它们的缺失不能缓解运动神经元的丧失。
