Hyde, D. R. | bioRxiv Science

bioRxiv2025

Regulation of Adult Zebrafish Retinal Regeneration by Lamβ1b-Chain-Containing Laminins

Retinal degenerative diseases are a major cause of blindness in humans that often result in permanent and progressive loss of vision. Unlike humans, zebrafish possess the remarkable ability to regenerate lost retinal neurons through Muller glia (MG) reprogramming and asymmetric cell division to produce multipotent retinal progenitor cells (RPCs). While most studies on the molecular mechanisms underlying this regeneration process have focused on intracellular mechanisms, the role of the microenvironment surrounding retinal cells, the extracellular matrix (ECM), has been understudied. Laminins are heterotrimeric glycoproteins, are principal components of the ECM basement membrane, and play important roles in vertebrate retinal development. Here, we examine the role of {beta}1b chain-containing laminins in the regenerative response of the zebrafish retina. We found that the zebrafish lamb1b gene is differentially expressed during MG reprogramming and MG and NPC proliferation during retinal regeneration. Further, we found that {beta}1b-containing laminins play important roles in regulating MG and NPC proliferation and neuroprotection of photoreceptors in light-damaged zebrafish retinas. Finally, Lam{beta}1b plays an important role in regulating the expression of integrin receptors and other laminin genes during the regeneration response. Taken together, Lam{beta}1b, and likely other ECM components, play a critical role in the MG-dependent neuronal regeneration response in the zebrafish retina.

neuroscience↗

bioRxiv2019

Inflammation and matrix metalloproteinase 9 (Mmp-9) regulate photoreceptor regeneration in the adult zebrafish

Brain injury activates complex inflammatory signals in dying neurons, surviving neurons, and glia. Here, we establish that inflammation regulates the regeneration of photoreceptors in the zebrafish retina and determine the cellular expression and function of the inflammatory protease, matrix metalloproteinase 9 (Mmp-9), during this regenerative neurogenesis. Following sterile photoreceptor ablation anti-inflammatory treatment suppresses both the number of injury-induced progenitors and regenerated photoreceptors. Upon photoreceptor injury, mmp-9 is induced in Muller glia, the intrinsic retinal stem cell, and Muller glia-derived photoreceptor progenitors. Deleting mmp-9 results in over production of injury-induced progenitors and regenerated photoreceptors, but over time the absence of Mmp-9 compromises the maturation and survival of the regenerated cones. Anti-inflammatory treatment in mutants rescues the defects in cone maturation and survival. These data provide a link between injury-induced inflammation in the vertebrate CNS, Mmp-9 function during photoreceptor regeneration and the requirement of Mmp-9 for the survival of regenerated cones. Significance StatementThe innate immune system is activated by neuronal death, and recent studies demonstrate that in zebrafish neuroinflammation is required for neuronal regeneration. The roles of inflammatory cytokines are being investigated, however, the function of the inflammatory protease, matrix metalloprotease Mmp-9, in neuronal regeneration is unknown. We show herein that in adult zebrafish retinal inflammation governs the proliferative phase of the stem cell-based regeneration of rod and cone photoreceptors and determine the specific roles for Mmp-9 in photoreceptor regeneration. This study provides the first mechanistic insights into the potential role of Mmp-9 and serves to link neuroinflammation, stem cell-based regeneration of photoreceptors and human photoreceptor disease.

neuroscience↗