TNF superfamily member APRIL enhances midbrain dopaminergic axon growth and contributes to the nigrostriatal projection &ITin vivo&IT
TNF superfamily member APRIL enhances midbrain dopaminergic axon growth and contributes to the nigrostriatal projection &ITin vivo&IT
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DOI：
10.1016/j.expneurol.2017.09.007
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发表时间：
2017-12-01
影响因子：
5.3
通讯作者：
Davies, Alun M.
中科院分区：
文献类型：
--
作者：
McWilliams, Thomas G.;Howard, Laura;Davies, Alun M.
我们在体外和体内研究了肿瘤坏死因子超家族成员APRIL在胚胎小鼠中脑多巴胺能神经元发育中的作用。在培养中，可溶性APRIL在E12和E14之间的发育窗口期促进轴突生长，此时黑质纹状体轴突在体内向纹状体中的目标生长。在这一时期和后期，纹状体和中脑都检测到四月转录本。APRIL的轴突生长促进作用与胶质细胞源性神经营养因子（GDNF）相似，但与GDNF相比，APRIL没有促进中脑多巴胺能神经元的存活。四月对轴突生长的影响可被其受体之一BCMA （TNFRSF13A）的功能阻断抗体所阻止，但不能被其另一受体TACI （TNFRSF13B）的功能阻断抗体所阻止，这表明四月对轴突生长的影响是由BCMA介导的。在体内，4 - / -胚胎的中脑多巴胺能向纹状体的投射密度与野生型仔鼠相比，在E14时显著降低。这些研究结果表明，APRIL是与黑质纹状体投射有关的生理因素。鉴于多巴胺能黑质纹状体连接的退化在帕金森病的发病和进展中的重要性，我们的研究结果有助于我们理解建立黑质纹状体完整性的因素。
We have studied the role of the tumor necrosis factor superfamily member APRIL in the development of embryonic mouse midbrain dopaminergic neurons in vitro and in vivo. In culture, soluble APRIL enhanced axon growth during a window of development between E12 and E14 when nigrostriatal axons are growing to their targets in the striatum in vivo. April transcripts were detected in both the striatum and midbrain during this period and at later stages. The axon growth-enhancing effect of APRIL was similar to that of glial cell-derived neurotrophic factor (GDNF), but in contrast to GDNF, APRIL did not promote the survival of midbrain dopaminergic neurons. The effect of APRIL on axon growth was prevented by function-blocking antibodies to one of its receptors, BCMA (TNFRSF13A), but not by function-blocking antibodies to the other APRIL receptor, TACI (TNFRSF13B), suggesting that the effects of APRIL on axon growth are mediated by BCMA. In vivo, there was a significant reduction in the density of midbrain dopaminergic projections to the striatum in April - / - embryos compared with wild type littermates at E14. These findings demonstrate that APRIL is a physiologically relevant factor for the nigrostriatal projection. Given the importance of the degeneration of dopaminergic nigrostriatal connections in the pathogenesis and progression of Parkinson's disease, our findings contribute to our understanding of the factors that establish nigrostriatal integrity.