Iron is important for life, and
iron deficiency impairs development, but whether the
iron level regulates neural differentiation remains elusive. In this study, with
iron-regulatory proteins (IRPs) knockout embryonic stem cells (ESCs) that showed severe
iron deficiency, we found that the Pax6- and Sox2-positive neuronal precursor cells and Tuj1 fibers in IRP1-/-IRP2-/- ESCs were significantly decreased after inducing neural differentiation. Consistently, in vivo study showed that the knockdown of IRP1 in IRP2-/- fetal mice remarkably affected the differentiation of neuronal precursors and the migration of neurons. These findings suggest that low intracellular
iron status significantly inhibits neurodifferentiation. When supplementing IRP1-/-IRP2-/- ESCs with
iron, these ESCs could differentiate normally. Further investigations revealed that the underlying mechanism was associated with an increase in
reactive oxygen species (ROS) production caused by the substantially low level of
iron and the down-regulation of
iron-
sulfur cluster
protein ISCU, which, in turn, affected the proliferation and differentiation of stem cells. Thus, the appropriate amount of
iron is crucial for maintaining normal neural differentiation that is termed ferrodifferentiation.