Carrel Tessa L, McWhorter Michelle L, Workman Eileen, Zhang Honglai, Wolstencroft Elizabeth C, Lorson Christian, Bassell Gary J, Burghes Arthur H M, Beattie Christine E
Center for Molecular Neurobiology, The Ohio State University, Columbus, Ohio 43210, USA.
J Neurosci. 2006 Oct 25;26(43):11014-22. doi: 10.1523/JNEUROSCI.1637-06.2006.
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.
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。SMN水平低下如何导致SMA尚不清楚。SMN在小核核糖核蛋白（snRNP）生物合成中发挥作用，但最近的研究表明，SMN也可能在轴突中发挥作用。我们之前表明，使用吗啉代寡核苷酸（MO）降低斑马鱼中的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方式，我们将smn MO与各种人类SMN RNA共注射，并检测对运动轴突的影响。野生型SMN可挽救斑马鱼中Smn减少引起的运动轴突缺陷。与这些缺陷在SMA中起作用一致，缺乏外显子7的SMN（SMN2基因的主要形式）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缩短相关。我们还表明，SMN外显子7中的保守区域QNQKE对运动轴突生长至关重要。为了研究对运动轴突生长重要的SMN功能，我们确定了不同形式的SMN进行寡聚化和结合Sm蛋白的能力，这是snRNP生物合成所需的功能。我们鉴定出了无法挽救运动轴突缺陷但保留snRNP功能的突变。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。这些数据表明，SMN在运动轴突中具有与SMA相关的新功能，且独立于snRNP生物合成。
