Hif1α-dependent hypoxia signaling contributes to the survival of deep-layer neurons and cortex formation in a mouse model

Hypoxia-inducible factor 1 alpha (Hif1 alpha) plays a crucial role in brain development. To study the function of Hif1 alpha in early brain development, we generated neuroepithelial cell-specific Hif1 alpha-knockout mice. Hif1 alpha-knockout mice died soon after birth; these mice exhibited an abnormal head shape, indicating the presence of brain defects. Morphological analysis revealed that Hif1 alpha ablation reduced the overall size of the brain, especially affecting the telencephalon. Neuronal apoptosis predominantly occurred in deep-layer neurons, consequently the alignment of cortical layers was severely disorganized in Hif1 alpha knockout mice. Furthermore, we demonstrated that Vegf signaling contributes to the survival of deep-layer neurons as a downstream effector of Hif1 alpha-dependent hypoxia signaling. Taken together, our findings demonstrate that Hif1 alpha plays a critical role in the early stages of telencephalon development.