Prion Protein Promotes Growth Cone Development through Reggie/Flotillin-Dependent N-Cadherin Trafficking
Prion Protein Promotes Growth Cone Development through Reggie/Flotillin-Dependent N-Cadherin Trafficking
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DOI：
10.1523/jneurosci.4729-11.2011
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发表时间：
2011-12-07
影响因子：
5.3
通讯作者：
Stuermer, Claudia A. O.
中科院分区：
文献类型：
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作者：
Bodrikov, Vsevolod;Solis, Gonzalo P.;Stuermer, Claudia A. O.
朊病毒蛋白 (PrP) 的作用尚未得到充分了解，部分原因是来自 C57BL/6J 小鼠的 PrP 缺陷 (-/-) 神经元似乎能够正常分化并且功能轻度受损。在这里，我们重新评估了这个概念，并意外地发现 PrP-/- 海马生长锥异常小，且丝状伪足和含有货物的囊泡很少。基于我们的发现，PrP-PrP 反式相互作用将 E-钙粘蛋白招募到细胞接触位点和 reggie 微域，并且 reggies 通过调节膜运输对生长至关重要，我们推断 PrP 和 reggie 可能通过 PrP 激活时的 PrP-reggie 连接信号传导（通过 PrP-Fc 诱导的反式相互作用）促进货物（N-钙粘蛋白）的递送。在野生型而非 PrP-/- 神经元中，PrP 激活导致 (1) PrP-reggie 共簇形成增强，(2) reggie 相关 fyn 和 MAP 激酶激活，(3) Exo70 和 N-钙粘蛋白（货物）招募到 reggie，(4) 生长锥偏好 PrP-Fc 作为底物，以及 (5) 更长的神经突。相反，PrP-reggie 诱导的 N-钙粘蛋白募集被突变体 TC10（reggie 下游的 GTP 酶）阻断，从而触发外囊辅助的货物递送。这意味着 PrP 在 reggie 介导的信号传导和货物运输中发挥作用，从而促进生长锥的复杂性和活力，从而促进生长锥伸长。
The role of prion protein (PrP) is insufficiently understood partially because PrP-deficient (-/-) neurons from C57BL/6J mice seem to differentiate normally and are functionally mildly impaired. Here, we reassessed this notion and, unexpectedly, discovered that PrP-/- hippocampal growth cones were abnormally small and poor in filopodia and cargo-containing vesicles. Based on our findings that PrP-PrP trans-interaction recruits E-cadherin to cell contact sites and reggie microdomains, and that reggies are essential for growth by regulating membrane trafficking, we reasoned that PrP and reggie might promote cargo (N-cadherin) delivery via PrP-reggie-connected signaling upon PrP activation (by PrP-Fc-induced trans-interaction). In wild-type but not PrP-/- neurons, PrP activation led to (1) enhanced PrP-reggie cocluster formation, (2) reggie-associated fyn and MAP kinase activation, (3) Exo70 and N-cadherin (cargo) recruitment to reggie, (4) the preference of the growth cone for PrP-Fc as substrate, and (5) longer neurites. Conversely, PrP-reggie-induced N-cadherin recruitment was blocked by mutant TC10, the GTPase downstream of reggie, triggering exocyst-assisted cargo delivery. This implies that PrP functions in reggie-mediated signaling and cargo trafficking, thus promoting growth cone complexity and vitality and thereby growth cone elongation.