Inflammation and Matrix Metalloproteinase 9 (Mmp-9) Function in the Zebrafish Retina

[摘要] Inflammation in the central nervous system (CNS) activates a complex network of signaling molecules in dying neurons, surviving neurons, and glia. In contrast to mammals, inflammatory signals in zebrafish are required for injury-induced neuronal regeneration in the forebrain. In the retina of zebrafish, Müller glia serve as the resident stem cell and the cellular origin for regenerative neurogenesis. Our lab previously identified the expression of an inflammatory protease known as matrix metalloproteinase 9 (mmp-9) following photoreceptor death (Calinescu et al., 2009). MMP-9 has many functions during CNS development and following injury, however, the function of Mmp-9 during zebrafish development and photoreceptor regeneration is unknown. The purpose of my dissertation was to use the zebrafish model to (1) determine how inflammation regulates Müller glia-derived photoreceptor regeneration in adults, (2) investigate the role of Mmp-9 as a component of the inflammatory response, and (3) determine potential developmental phenotypes in the absence of mmp-9. My results show that genes encoding inflammatory molecules are strongly induced by photoreceptor death, and anti-inflammatory treatment suppresses both the number of injury-induced progenitors and regenerated photoreceptors. Following photoreceptor injury and death, mmp-9 is expressed in Müller glia, the intrinsic retinal stem cell, and Müller glia-derived photoreceptor progenitors. Deleting mmp-9 results in an over production of injury-induced progenitors and regenerated photoreceptors, but compromises the maturation and survival of regenerated cones. These data provide a link between injury-induced inflammation in the vertebrate CNS and Mmp-9 function during photoreceptor regeneration.Chapter one begins with a brief overview of our current understanding of regulators that govern Müller glia entry into the cell cycle and progenitor proliferation. Next, I discuss inflammatory mechanisms that govern neurogenesis in vertebrates, and finally I review the key literature about the inflammatory protease, Mmp-9. In chapter two, I present data supporting the role for injury-induced inflammation and Mmp-9 function governing photoreceptor regeneration.In chapter three, I characterize additional mmp-9 mutants and developmental phenotypes associated with the two mutants used in studies from chapter two. Finally, I conclude with a brief discussion of future experiments based on my dissertation work. Together, my work provides a link between injury-induced inflammation in the vertebrate CNS and Mmp-9 function during photoreceptor regeneration.

[发布机构] University of Michigan

[效力级别] Retina

[关键词] Regeneration;Retina;Zebrafish;Inflammation;Matrix Metalloproteinase 9 (Mmp-9);Science (General);Science;Neuroscience