Regulation of the lncRNA malat1/Egr1 Axis by Wnt, Notch and TGF-β signaling: A Key Mechanism in Retina Regeneration

Abstract

Adult zebrafish retinas rely on the resident Muller glia to maintain homeostasis and enable regeneration. Retina regeneration remains incomplete in mammals despite extensive efforts to emulate zebrafish regenerative conditions. Many studies have examined the reprogramming of zebrafish Muller glia cells, which is necessary for regeneration driven by regeneration-associated gene expression. Here, we show that the lncRNA malat1, crucial for many biological functions, plays essential roles during retina regeneration. We demonstrate that malat1 functions through an Egr-dependent axis, modulated by Wnt, Notch, and TGF-{beta} signaling pathways, and is necessary for effective retina regeneration. 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-{beta} signaling stabilize Malat1 in mice while the same signaling destabilizes malat1 in zebrafish. Taken together, our work uncovers a new role for the malat1/Egr1 axis in necessitating retina regeneration, which may have important implications for differential regenerative ability in vertebrates.