Neurodevelopment requires precise regulation of gene expression, including post-transcriptional regulatory events such as alternative splicing and mRNA translation. However, translational regulation of specific isoforms during neurodevelopment and the mechanisms behind it remain unknown. Using RNA-seq analysis of mouse neocortical polysomes, here we report translationally repressed and derepressed mRNA isoforms during neocortical neurogenesis whose orthologs include risk genes for neurodevelopmental disorders. We demonstrate that the translation of distinct mRNA isoforms of the RNA binding protein (RBP), Elavl4, in radial glia progenitors and early neurons depends on its alternative 5′ UTRs. Furthermore, 5′ UTR-driven Elavl4 isoform-specific translation depends on upstream control by another RBP, Celf1. Celf1 regulation of Elavl4 translation dictates development of glutamatergic neurons. Our findings reveal a dynamic interplay between distinct RBPs and alternative 5′ UTRs in neuronal development and underscore the risk of post-transcriptional dysregulation in co-occurring neurodevelopmental disorders.

神经发育需要基因表达的精确调节，包括转录后调节事件，例如选择性剪接和 mRNA 翻译。然而，神经发育过程中特定亚型的翻译调节及其背后的机制仍然未知。通过对小鼠新皮质多核糖体的 RNA-seq 分析，我们报告了新皮质神经发生过程中翻译抑制和去抑制的 mRNA 亚型，其直系同源物包括神经发育障碍的风险基因。我们证明，RNA 结合蛋白 (RBP) Elavl4的不同 mRNA 亚型在放射状胶质祖细胞和早期神经元中的翻译取决于其替代的 5' UTR。此外，5' UTR 驱动的Elavl4同工型特异性翻译依赖于另一个 RBP（Celf1）的上游控制。Celf1 对Elavl4翻译的调节决定了谷氨酸能神经元的发育。我们的研究结果揭示了神经元发育中不同 RBP 和替代 5' UTR 之间的动态相互作用，并强调了同时发生的神经发育障碍中转录后失调的风险。