RNA-binding protein Sam68 controls synapse number and local β-actin mRNA metabolism in dendrites
RNA-binding protein Sam68 controls synapse number and local β-actin mRNA metabolism in dendrites
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DOI：
10.1073/pnas.1209811110
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发表时间：
2013-02-19
影响因子：
11.1
通讯作者：
Jordan, Bryen A.
中科院分区：
文献类型：
--
作者：
Klein, Matthew E.;Younts, Thomas J.;Jordan, Bryen A.
适当的突触功能需要通过RNA结合蛋白（rbp）交易的RNA代谢的空间和时间区隔化。RBP活性的丧失导致异常的转录后调节，并导致多种神经系统疾病，其潜在的突触形态和传递缺陷。与有丝分裂（Sam68）相关的68-kDa RBP Src的功能丧失与神经系统疾病脆性X震颤/共济失调综合征的发病机制有关。Sam68结合β -肌动蛋白（actb）的mRNA，这是树突棘的整体细胞骨架成分。我们发现，在原代海马培养中，Sam68敲除或破坏Sam68与其actb mRNA货物之间的结合会减少突触树突室中actb mRNA的数量，并导致树突棘减少。与这些观察结果一致，我们发现Sam68- ko小鼠与突触多体相关的actb mRNA水平降低，突触actb蛋白水平降低，这表明Sam68促进了体内突触中actb mRNA的翻译。此外，经形态学和功能评估，体内Sam68基因敲除或急性敲除会导致海马形成中的兴奋性突触减少。因此，我们提出Sam68通过控制突触后actb mRNA代谢以细胞自主的方式调节突触数量。我们的研究确定了Sam68在actb突触树突转录后调控中的作用，并可能为脆性X震颤/共济失调综合征的病理生理学提供见解。
Proper synaptic function requires the spatial and temporal compartmentalization of RNA metabolism via transacting RNA-binding proteins (RBPs). Loss of RBP activity leads to abnormal posttranscriptional regulation and results in diverse neurological disorders with underlying deficits in synaptic morphology and transmission. Functional loss of the 68-kDa RBP Src associated in mitosis (Sam68) is associated with the pathogenesis of the neurological disorder fragile X tremor/ataxia syndrome. Sam68 binds to the mRNA of beta-actin (actb), an integral cytoskeletal component of dendritic spines. We show that Sam68 knockdown or disruption of the binding between Sam68 and its actb mRNA cargo in primary hippocampal cultures decreases the amount of actb mRNA in the synaptodendritic compartment and results in fewer dendritic spines. Consistent with these observations, we find that Sam68-KO mice have reduced levels of actb mRNA associated with synaptic polysomes and diminished levels of synaptic actb protein, suggesting that Sam68 promotes the translation of actb mRNA at synapses in vivo. Moreover, genetic knockout of Sam68 or acute knockdown in vivo results in fewer excitatory synapses in the hippocampal formation as assessed morphologically and functionally. Therefore, we propose that Sam68 regulates synapse number in a cell-autonomous manner through control of postsynaptic actb mRNA metabolism. Our research identifies a role for Sam68 in synaptodendritic posttranscriptional regulation of actb and may provide insight into the pathophysiology of fragile X tremor/ataxia syndrome.