ΔfosB is an alternatively spliced product of the FosB gene that is essential for dopamine-induced reward pathways and that acts as a master switch for addiction. However, the molecular mechanisms of its generation and regulation by dopamine signaling are unknown. Here, we report that dopamine D1 receptor signaling synergizes with the activin/ALK4/Smad3 pathway to potentiate the generation of ΔFosB mRNA in medium spiny neurons (MSNs) of the nucleus accumbens (NAc) via activation of the RNA-binding protein PCBP1, a regulator of mRNA splicing. Concurrent activation of PCBP1 and Smad3 by D1 and ALK4 signaling induced their interaction, nuclear translocation, and binding to sequences in exon-4 and intron-4 of FosB mRNA. Ablation of either ALK4 or PCBP1 in MSNs impaired ΔFosB mRNA induction and nuclear translocation of ΔFosB protein in response to repeated co-stimulation of D1 and ALK4 receptors. Finally, ALK4 is required in NAc MSNs of adult mice for behavioral sensitization to cocaine. These findings uncover an unexpected mechanism for ΔFosB generation and drug-induced sensitization through convergent dopamine and ALK4 signaling.

中文翻译：

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PCBP1 的汇聚多巴胺和 ALK4 信号控制 FosB 选择性剪接和可卡因行为敏化

ΔfosB 是 FosB 基因的选择性剪接产物，对于多巴胺诱导的奖赏途径至关重要，并且充当成瘾的主开关。然而，其产生和多巴胺信号传导调节的分子机制尚不清楚。在这里，我们报告多巴胺 D1 受体信号传导与激活素/ALK4/Smad3 通路协同作用，通过激活 RNA 结合蛋白 PCBP1，增强伏隔核 (NAc) 中型多棘神经元 (MSN) 中 ΔFosB mRNA 的生成。mRNA 剪接的调节因子。D1 和 ALK4 信号传导同时激活 PCBP1 和 Smad3 会诱导它们之间的相互作用、核转位以及与 FosB mRNA 外显子 4 和内含子 4 中的序列的结合。MSN 中 ALK4 或 PCBP1 的消融会损害 ΔFosB mRNA 诱导以及响应 D1 和 ALK4 受体重复共刺激的 ΔFosB 蛋白核转位。最后，成年小鼠的 NAc MSN 中需要 ALK4 才能对可卡因行为敏感。这些发现揭示了通过聚合多巴胺和 ALK4 信号传导产生 ΔFosB 和药物诱导致敏的意想不到的机制。