Abstract
Purpose :
Vascular development and remodeling is a complex process that is well orchestrated by multiple signaling pathways and light. In the developing eye, it has been shown that light regulates hyaloid vessel regression via Opsin proteins to control VEGFA and dopamine levels. Dopamine promotes Hyaloid regression, VEGFA inhibits it. In this study, we investigated the downstream effectors of the VEGFA and Dopamine and how these two opposing signaling pathways coordinate to control timing of the hyaloid vessel in response to light.
Methods :
The Hippo pathway effector YAP is a transcription co-factor that functions to promote cell survival. We hypothesize that YAP mediates the light signal to regulate vascular regression timing. To test this hypothesis, we first examined YAP cellular localization during hyaloid vessel regression. Next, we examined whether nuclear YAP is sufficient to inhibit hyaloid vessel regression. We further investigated whether VEGFA and dopamine can regulate YAP cellular localization and how these two opposing events controls YAP cellular localization by using genetic mouse models including Drd2 and Gnas. Lastly, we examined whether violate light can regulate YAP cellular localization directly through neuropsin (OPN5).
Results :
Nuclear YAP in hyaloid endothelial cells (ECs) of YAP transgenic and Lats1/2 mutant is sufficient to inhibit hyaloid regression. VEGFA promotes and dopamine inhibits YAP nuclear localization. Dopamine receptor DRD2 blocks YAP activity through inhibition of VEGFA and activation of Gs alpha subunit. Violate light is sufficient to keep YAP remaining in the cytoplasm mediated by retinal dopamine signaling in adjacent hyaloid VECs.
Conclusions :
Our study demonstrated that Hippo pathway effector YAP is an integration nexus to mediate the opposing OPN4-VEGFA and OPN5-dopamine pathways in VECs to regulate hyaloid regression. These results reveal an unexpectedly direct role of light sensing in the regulation of cell death and developmental timing via the Hippo pathway.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.