Nonsense-mediated mRNA decay orchestrates neuronal migration and cortical lamination while modulating Reelin and ciliary gene regulatory networks.

Nonsense-mediated mRNA decay (NMD) is associated with neurodevelopmental disorders, yet its role in cortical organization is unknown. We demonstrate that NMD mediated by UPF2 is indispensable for cortical organization. Conditional deletion of Upf2 in radial glial cells delays neuronal migration and disrupts cortical lamination. Trp53 knockout rescues microcephaly from Upf2 deficiency but cannot rescue lamination defects, showing that UPF2's role in neuronal migration is uncoupled from its regulation of cell cycle and independent of p53. UPF2 deficiency downregulates key neuronal migration genes in the Reelin signaling pathway and microtubule assembly (e.g., Dab1, Lrp8, Tubb2b, and Tuba1a), partly through upregulation of the transcriptional repressor Ino80. Additionally, NMD inhibition induces widespread upregulation of ciliary genes. Ectopic expression of Foxj1, a master regulator of ciliary genes and an NMD target, impedes neuronal migration, phenocopying Upf2 loss. Therefore, NMD is a central post-transcriptional mechanism coordinating migration and ciliary gene networks crucial for cortical structure development.