Menin orchestrates corticogenesis via epigenetic activation of EphA4 in late-born neurons

The development of the mammalian cerebral cortex is tightly regulated by epigenetic mechanisms. However, the role of epigenetic modifications in gene regulation and their impact on neocortical function remain poorly understood. Here, we demonstrate that Menin, encoded by the multiple endocrine neoplasia type 1 (Men1) gene, is essential for neurogenesis. Deficiency in Men1 disrupts the formation of the laminated neocortex, particularly in the upper-layer neurons. In Men1-deficient late-born neurons, migration to their final positions is impaired, accompanied by defective neuronal polarization. Mechanistic studies reveal that Menin regulates global chromatin accessibility at transcriptional start sites of genes critical for neuronal development. The loss function of Menin primarily reduces H3K4me3 deposition at promoter regions. Notably, complementation with EphA4 in late-born neurons mitigates polarization defects in the context of Men1 deficiency. These findings support the importance of Menin in corticogenesis, providing insight into the formation of the cerebral cortex.