Survival motor neuron function in motor axons is independent of functions required for small nuclear ribonucleoprotein biogenesis
Survival motor neuron function in motor axons is independent of functions required for small nuclear ribonucleoprotein biogenesis
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DOI：
10.1523/jneurosci.1637-06.2006
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发表时间：
2006-10-25
影响因子：
5.3
通讯作者：
Beattie, Christine E.
中科院分区：
文献类型：
--
作者：
Carrel, Tessa L.;McWhorter, Michelle L.;Beattie, Christine E.
脊髓性肌萎缩症（SMA）是一种由存活运动神经元（SMN）蛋白水平低下引起的运动神经元退行性疾病，与SMN1的突变或缺失以及SMN2的保留有关。低水平的SMN如何导致SMA尚不清楚。SMN在小核核糖核蛋白（snRNP）的生物发生中起作用，但最近的研究表明SMN也可能在轴突中起作用。我们之前的研究表明，使用morpholinos （MO）降低斑马鱼的Smn水平会导致运动轴突缺陷。为了确定Smn在运动轴突生长中的作用，我们将Smn MO与各种人类Smn rna共注射，并分析了对运动轴突的影响。野生型SMN可修复斑马鱼因SMN减少而引起的运动轴突缺陷。与这些在SMA中发挥作用的缺陷一致，SMN缺乏SMN2基因的主要形式外显子7和人类SMA突变不能挽救有缺陷的运动轴突。此外，运动轴突缺陷的严重程度与寿命下降有关。我们还发现SMN外显子7中的一个保守区域QNQKE对运动轴突的生长至关重要。为了研究SMN在运动轴突生长中的重要功能，我们确定了不同形式的SMN寡聚化和结合Sm蛋白的能力，这是snRNP生物发生所需的功能。我们发现突变不能挽救运动轴突缺陷，但保留snRNP功能。因此，我们已经将SMN的snRNP功能与其在运动轴突中的功能分离开来。这些数据表明，SMN在运动轴突中具有与SMA相关的新功能，并且独立于snRNP的生物合成。
Spinal muscular atrophy (SMA) is a motor neuron degenerative disease caused by low levels of the survival motor neuron (SMN) protein and is linked to mutations or loss of SMN1 and retention of SMN2. How low levels of SMN cause SMA is unclear. SMN functions in small nuclear ribonucleoprotein ( snRNP) biogenesis, but recent studies indicate that SMN may also function in axons. We showed previously that decreasing Smn levels in zebrafish using morpholinos ( MO) results in motor axon defects. To determine how Smn functions in motor axon outgrowth, we coinjected smn MO with various human SMN RNAs and assayed the effect on motor axons. Wild-type SMN rescues motor axon defects caused by Smn reduction in zebrafish. Consistent with these defects playing a role in SMA, SMN lacking exon 7, the predominant form from the SMN2 gene, and human SMA mutations do not rescue defective motor axons. Moreover, the severity of the motor axon defects correlates with decreased longevity. We also show that a conserved region in SMN exon 7, QNQKE, is critical for motor axon outgrowth. To address the function of SMN important for motor axon outgrowth, we determined the ability of different SMN forms to oligomerization and bind Sm protein, functions required for snRNP biogenesis. We identified mutations that failed to rescue motor axon defects but retained snRNP function. Thus, we have dissociated the snRNP function of SMN from its function in motor axons. These data indicate that SMN has a novel function in motor axons that is relevant to SMA and is independent of snRNP biosynthesis.