Synaptic targeting with subcellular specificity is essential for neural circuit assembly. Developing neurons use mechanisms to curb promiscuous synaptic connections and to direct synapse formation to defined subcellular compartments. How this selectivity is achieved molecularly remains enigmatic. Here, we discover a link between mRNA poly(A)-tailing and axon collateral branch-specific synaptic connectivity within the CNS. We reveal that the RNA-binding protein Musashi binds to the mRNA encoding the receptor protein tyrosine phosphatase Ptp69D, thereby increasing poly(A) tail length and Ptp69D protein levels. This regulation specifically promotes synaptic connectivity in one axon collateral characterized by a high degree of arborization and strong synaptogenic potential. In a different compartment of the same axon, Musashi prevents ectopic synaptogenesis, revealing antagonistic, compartment-specific functions. Moreover, Musashi-dependent Ptp69D regulation controls synaptic connectivity in the olfactory circuit. Thus, Musashi differentially shapes synaptic connectivity at the level of individual subcellular compartments and within different developmental and neuron type-specific contexts.

具有亚细胞特异性的突触靶向对于神经回路组装至关重要。发育中的神经元使用机制来抑制混杂的突触连接并将突触形成引导到定义的亚细胞区室。如何在分子上实现这种选择性仍然是个谜。在这里，我们发现了中枢神经系统内 mRNA poly(A)-tailing 和轴突侧枝分支特异性突触连接之间的联系。我们揭示了 RNA 结合蛋白 Musashi 与编码受体蛋白酪氨酸磷酸酶 Ptp69D 的 mRNA 结合，从而增加了 poly(A) 尾长和 Ptp69D 蛋白水平。这一规定特别促进了一个轴突侧枝中的突触连接，其特点是高度树枝化和强大的突触形成潜力。在同一轴突的不同隔间，Musashi 防止异位突触发生，揭示拮抗的、隔室特异性功能。此外，Musashi 依赖性 Ptp69D 调节控制嗅觉回路中的突触连接。因此，Musashi 在单个亚细胞区室的水平上以及在不同的发育和神经元类型特定的环境中不同地塑造突触连接。