A novel role for the DNA repair gene Rad51 in Netrin-1 signalling.
A novel role for the DNA repair gene Rad51 in Netrin-1 signalling.
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DOI：
10.1038/srep39823
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发表时间：
2017-01-06
影响因子：
4.6
通讯作者：
Jasoni CL
中科院分区：
文献类型：
--
作者：
Glendining KA;Markie D;Gardner RJ;Franz EA;Robertson SP;Jasoni CL
RAD 51的突变最近与人类先天性镜像运动（CMM）有关，这是一种运动系统发育障碍。之前与CMM相关的唯一基因编码Netrin-1受体DCC，这对于皮质脊髓和胼胝体轴突束的形成很重要。因此，我们假设Rad 51在Netrin-1介导的轴突发育中具有新的作用。在小鼠初级运动皮层神经元中，Rad 51蛋白响应Netrin-1而沿轴突远端重新分布，进一步表明两者之间存在功能联系。我们接下来操纵Rad 51表达，并评估Netrin-1反应性。Rad 51 siRNA敲除增强了Netrin-1介导的神经突分支和丝状伪足形成。RAD 51过表达抑制了这些反应，而CMM连锁的R250 Q突变（预测的功能丧失）的过表达则没有影响。因此，Rad 51似乎负调节Netrin-1信号传导。最后，我们研究了Rad 51是否可能通过调节Unc 5家族的表达来发挥作用，Unc 5家族是Netrin-1反应性的已知负调节因子。Unc 5 b和Unc 5c转录下调响应Rad 51敲低，上调与RAD 51过表达，但不是R250 Q。因此，Rad 51至少部分地通过调节Unc 5s的表达来负调节Netrin-1信号传导。积极和消极影响的不平衡可能导致运动系统发育异常，从而导致CMM。
Mutations in RAD51 have recently been linked to human Congenital Mirror Movements (CMM), a developmental disorder of the motor system. The only gene previously linked to CMM encodes the Netrin-1 receptor DCC, which is important for formation of corticospinal and callosal axon tracts. Thus, we hypothesised that Rad51 has a novel role in Netrin-1-mediated axon development. In mouse primary motor cortex neurons, Rad51 protein was redistributed distally down the axon in response to Netrin-1, further suggesting a functional link between the two. We next manipulated Rad51 expression, and assessed Netrin-1 responsiveness. Rad51 siRNA knockdown exaggerated Netrin-1-mediated neurite branching and filopodia formation. RAD51 overexpression inhibited these responses, whereas overexpression of the CMM-linked R250Q mutation, a predicted loss-of-function, had no effect. Thus, Rad51 appears to negatively regulate Netrin-1 signalling. Finally, we examined whether Rad51 might operate by modulating the expression of the Unc5 family, known negative regulators of Netrin-1-responsiveness. Unc5b and Unc5c transcripts were downregulated in response to Rad51 knockdown, and upregulated with RAD51 overexpression, but not R250Q. Thus, Rad51 negatively regulates Netrin-1 signalling, at least in part, by modulating the expression of Unc5s. Imbalance of positive and negative influences is likely to lead to aberrant motor system development resulting in CMMs.
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DOI：
10.1523/jneurosci.5254-10.2011
发表时间：
2011-02-09
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Kim D;Ackerman SL
通讯作者：
Ackerman SL
影响因子：
14.9
作者：
Park, Jung-Young;Yoo, Han-Wook;Kim, Bok-Ryang;Park, Raekil;Choi, Sang-Yun;Kim, Youngho
通讯作者：
Kim, Youngho
影响因子：
5.3
作者：
Dent, EW;Barnes, AM;Kalil, K
通讯作者：
Kalil, K
影响因子：
3.7
作者：
Fothergill, Thomas;Donahoo, Amber-Lee S.;Richards, Linda J.
通讯作者：
Richards, Linda J.
影响因子：
9.9
作者：
Depienne, C.;Cincotta, M.;Roze, E.
通讯作者：
Roze, E.