Regulation of the lncRNA malat1 /Egr1 axis by Wnt, Notch, and TGF-β signaling: a key mechanism in retina regeneration

Unlike mammals, upon injury, adult zebrafish retinas rely on their ability to reprogram resident Müller glia to progenitor cells, enabling regeneration and restoration of vision. Retina regeneration remains incomplete in mammals despite extensive efforts to stimulate zebrafish regenerative conditions. Here, we show that the zebrafish lncRNA malat1 (metastasis-associated lung adenocarcinoma transcript 1), crucial for many biological functions, plays essential roles during retina regeneration. We demonstrate that zebrafish malat1 functions through an Egr1-dependent axis, modulated by Wnt, Notch, and TGF-β signaling pathways, and is necessary for effective retina regeneration. We performed RNA immunoprecipitation to establish the association of zebrafish malat1 with epigenetic modifiers Ezh2 and Hdac1 in the regenerating retina. Moreover, we uncover that the antisense lncRNA talam1, which regulates malat1 availability, is differentially regulated in zebrafish and mice, highlighting species-specific gene regulatory mechanisms after retinal injury. Cells with active TGF-β signaling stabilize mouse Malat1 while the same signaling destabilizes zebrafish malat1. Our findings uncover a previously unknown role of malat1/Egr1 axis as a crucial regulator of retina regeneration, shedding light on its possible influence on the different regenerative abilities of vertebrates.