A ROS/HIF-1α/JMY signaling axis drives radiation-induced migration and invasion of neural progenitor cells

Neural progenitor cell (NPC) migration is essential for proper cortical development, and its disruption contributes to severe brain malformations such as lissencephaly, polymicrogyria, and microcephaly. Although abnormal neuronal migration has been reported in irradiated embryos, the molecular mechanisms by which ionizing radiation affects NPC motility remain poorly understood.

Fetal human and mouse NPCs were exposed to low doses of ionizing radiation (0.5-3 Gy). Migratory and invasive properties were assessed both in vitro and in vivo. Reactive oxygen species (ROS) production was monitored shortly after irradiation, and downstream signaling pathways were investigated through analysis of HIF-1α nuclear accumulation and expression of Junction-mediating and regulatory protein (JMY). Functional involvement of HIF-1α and JMY was tested using pharmacological or molecular inhibition approaches.

Ionizing radiation rapidly enhanced the migratory and invasive capacity of fetal human and mouse NPCs in vitro and in vivo. This response was preceded by an early increase in endogenous ROS, which initiated the migratory phenotype. Mechanistically, radiation-induced ROS promoted nuclear accumulation of HIF-1α, leading to upregulation of JMY, an actin nucleation-promoting factor that drives cytoskeletal remodeling and cell motility. Inhibition of either HIF-1α or JMY abolished the radiation-induced increase in NPC migration and invasion, identifying a conserved ROS/HIF-1α/JMY signaling axis as a key mediator of this effect.

These findings reveal that low-dose ionizing radiation stimulates NPC migration and invasion through activation of a ROS/HIF-1α/JMY pathway. Given the critical requirement for tightly regulated NPC migration during brain morphogenesis, aberrant activation of this signaling axis may contribute to radiation-induced neurodevelopmental disorders.