Brain-formed estrogen promotes retinal regeneration in zebrafish via nuclear estrogen receptor-dependent genomic signaling.

Zebrafish are known to possess the ability to generate new neurons in the retina throughout life, similar to what is observed in the brain. Notably, brain aromatase (AroB) expressed in radial glial cells (RGCs) is associated with the high neuroregenerative capacity of zebrafish. While AroB is known to be present in the zebrafish eye, its role in retinal regeneration remains unclear. In this study, we are the first to demonstrate the cellular localization and potential function of AroB, together with the involvement of estrogen receptors (ERs), in the injured zebrafish retina. We successfully identified that AroB is not exclusively expressed in Müller glial (MG) cells, but also in interneuronal cells, photoreceptor cells, and lens epithelial cells. Furthermore, we showed that the addition of estradiol (E2) increased AroB expression and altered its distribution, resulting in a positive signal located in ganglion cells. We also demonstrated that E2 acts as a neuroprotective and neuroregenerative agent by decreasing the number of apoptotic cells and increasing the number of proliferating cells in the injured retina. In addition, we provide evidence that AroB is involved in stimulating MG cell activation in response to retinal injury. Finally, the effects of E2 on apoptosis and proliferation in the injured retina were blocked by ER antagonists, but not by the G-protein-coupled estrogen receptor (GPER) antagonist. Altogether, our findings strongly suggest that E2 produced in the eye by AroB, along with its downstream signaling through genomic pathways, contributes to the robust regenerative capacity of the zebrafish retina following injury.