Ferrero Restelli Facundo, Federicci Fernando, Ledda Fernanda, Paratcha Gustavo
Division de Neurociencia Molecular y Celular, Instituto de Biología Celular y Neurociencias Prof. E. De Robertis (IBCN), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina.
Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires, CONICET, Buenos Aires, Argentina.
Front Mol Neurosci. 2023 Feb 2;16:1090824. doi: 10.3389/fnmol.2023.1090824. eCollection 2023.
Glucocorticoids (GC) affect neuronal plasticity, development and function of the nervous system by inhibiting neurotrophin-induced Trk signaling. It has been established that pretreatment with dexamethasone (DEX) restricts Neurotrophin-induced neurite outgrowth by inhibiting Trk-dependent activation of Ras-Erk1/2 signaling pathways. However, the precise molecular mechanism through which DEX interferes with neurotrophin signaling and Trk-mediated neurite outgrowth has not been clearly defined yet. Here, we observed that in PC12 cells DEX treatment promotes the transcription of Sprouty4, a regulatory molecule that is part of a negative feedback module that specifically abrogates Ras to Erk1/2 signaling in response to NGF. In line with this, either knockdown of or overexpression of a dominant negative form of Sprouty4 (Y53A), rescue the inhibition of NGF/TrkA-promoted neurite outgrowth and Erk1/2 phosphorylation induced by DEX. Likewise, treatment of hippocampal neurons with DEX induces the expression of Sprouty4 and its knockdown abrogates the inhibitory effect of DEX on primary neurite formation, dendrite branching and Erk1/2 activation induced by BDNF. Thus, these results suggest that the induction of mRNA by DEX translates into a significant inhibition of Trk to Erk1/2 signaling pathway. Together, these findings bring new insights into the crosstalk between DEX and neurotrophin signaling and demonstrate that Sprouty4 mediates the inhibitory effects of DEX on neurotrophin function.
糖皮质激素（GC）通过抑制神经营养因子诱导的Trk信号传导来影响神经元可塑性、神经系统的发育和功能。已经确定，地塞米松（DEX）预处理通过抑制Ras-Erk1/2信号通路的Trk依赖性激活来限制神经营养因子诱导的神经突生长。然而，DEX干扰神经营养因子信号传导和Trk介导的神经突生长的确切分子机制尚未明确界定。在这里，我们观察到在PC12细胞中，DEX处理促进了Sprouty4的转录，Sprouty4是一种调节分子，是负反馈模块的一部分，该模块可特异性消除对神经生长因子（NGF）作出反应的Ras至Erk1/2信号传导。与此一致的是，敲低Sprouty4或过表达其显性负性形式（Y53A），可挽救DEX对NGF/TrkA促进的神经突生长和Erk1/2磷酸化的抑制作用。同样，用DEX处理海马神经元可诱导Sprouty4的表达，敲低该基因可消除DEX对脑源性神经营养因子（BDNF）诱导的初级神经突形成、树突分支和Erk1/2激活的抑制作用。因此，这些结果表明，DEX诱导Sprouty4 mRNA表达转化为对Trk至Erk1/2信号通路的显著抑制。总之，这些发现为DEX与神经营养因子信号传导之间的相互作用带来了新的见解，并证明Sprouty4介导了DEX对神经营养因子功能的抑制作用。
