Redox signalingvialipid peroxidation regulates retinal progenitor cell differentiation

SummaryReactive oxygen species (ROS) and downstream products of lipid oxidation are emerging as important secondary messengers in tissue homeostasis. However their regulation and mechanism of action remain poorly studiedin vivoduring normal development. Here we reveal that the fine regulation of hydrogen peroxide (H2O2) levels at the degradation step by its scavenger Catalase is crucial to mediate the switch from proliferation to differentiation in retinal progenitor cells (RPCs). We further show that altering the levels of downstream products of the Redox signaling can also affect this switch. Indeed, we identify9-hydroxystearic acid (9-HSA), an endogenous downstream lipid peroxidation product, as a mediator of this effect in the zebrafish retina. In fact, RPCs exposed to higher amounts of9-HSA failed to differentiate and remained proliferative. We found that9-HSA exerts its biological functionin vivoby inhibiting the activity of histone deacetylase 1. We finally show that the local and temporal manipulation of H2O2levels bycatalaseoverexpression in RPCs was sufficient to trigger their premature differentiation. Therefore the amount of H2O2in RPCs is instructive of their ability to switch from proliferation to differentiation. We propose a mechanism that acts in RPC and linking H2O2homeostasis and neuronal differentiationviathe modulation of lipid peroxidation.