let-7 MicroRNA-Mediated Regulation of Shh Signaling and the Gene Regulatory Network Is Essential for Retina Regeneration

Summary Upon injury, Müller glia cells of the zebrafish retina reprogram themselves to progenitor cells with stem cell characteristics. This necessity for retina regeneration is often compromised in mammals. We explored the significance of developmentally inevitable Sonic hedgehog signaling and found its necessity in MG reprogramming during retina regeneration. We report on stringent translational regulation of sonic hedgehog, smoothened, and patched1 by let-7 microRNA, which is regulated by Lin28a, in Müller glia (MG)-derived progenitor cells (MGPCs). We also show Shh-signaling-mediated induction of Ascl1 in mouse and zebrafish retina. Moreover, Shh-signaling-dependent regulation of matrix metalloproteinase9, in turn, regulates Shha levels and genes essential for retina regeneration, such as lin28a, zic2b, and foxn4. These observations were further confirmed through whole-retina RNA-sequencing (RNA-seq) analysis. This mechanistic gene expression network could lead to a better understanding of retina regeneration and, consequently, aid in designing strategies for therapeutic intervention in human retinal diseases.

Graphical Abstract

Highlights • Shh signaling is essential for MG dedifferentiation during retina regeneration • Shh signaling components are regulated by let-7 microRNA in the zebrafish retina • A regulatory feedback loop between Mmp9 and Shh signaling is active in the retina • Shh signaling induced a gene-regulatory network involving mmp9, ascl1a, zic2b, and foxn4

Kaur et al. demonstrate that microRNA let-7 in injured zebrafish retina regulates the translation of shha, shhb, smo, ptch1, and zic2b mRNAs. Further, Shh signaling is necessary during retina regeneration for inducing a pro-regenerative gene expression cascade involving several genes, including ascl1a, lin28a, mmp9, foxn4, and zic2b.