Maternal Hyperglycemia Disrupts Cerebral Cortex Development Through the Foxp1-Dll1-Notch Axis

Maternal hyperglycemia is associated with adverse neurodevelopmental outcomes in offspring, but the mechanisms by which it affects fetal brain development remain incompletely understood. Using a mouse model of pregestational diabetes mellitus (PGDM), we found that maternal hyperglycemia was associated with reduced cortical thickness and altered cortical lamination. These abnormalities were accompanied by changes in neural stem cell differentiation and asymmetric division, as well as impaired neuronal migration and dendritic development. Transcriptomic analysis identified the transcription factor Foxp1 as markedly downregulated in the PGDM embryonic cortex. Restoring Foxp1 expression in vivo substantially alleviated the observed cortical abnormalities. Mechanistic experiments showed that Foxp1 represses transcription of the Notch ligand Delta-like 1 (Dll1) and attenuates Notch signaling. Together, these findings implicate the Foxp1-Dll1-Notch axis as one pathway contributing to disrupted corticogenesis in the PGDM model and provide insight into how an adverse intrauterine metabolic environment affects embryonic brain development.