Redox Signaling via Lipid Peroxidation Regulates Retinal Progenitor Cell Differentiation

Abstract

Reactive 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 studied in vivo during normal development. Here, we reveal that the fine regulation of hydrogen peroxide (H₂O₂) levels by its scavenger Catalase to mediate the switch from proliferation to differentiation in retinal progenitor cells (RPCs) is crucial. We identify 9-hydroxystearic acid (9-HSA), an endogenous downstream lipid peroxidation product, as a mediator of this effect in the zebrafish retina. We show that the 9-HSA proliferative effect is due to the activation of Notch and Wnt pathways through the inhibition of the histone deacetylase 1. We show that the local and temporal manipulation of H₂O₂ levels in RPCs is sufficient to trigger their premature differentiation. We finally propose a mechanism that links H₂O₂ homeostasis and neuronal differentiation via the modulation of lipid peroxidation.

Keywords: 9-hydroxystearic acid; H(2)O(2); HDAC1; lipid peroxidation; neuronal differentiation; redox signaling; retinal progenitor cells; stem cell metabolism; zebrafish.