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 photoreceptor ablation, anti-inflammatory treatment suppresses the number of injury-induced progenitors and regenerated photoreceptors. Upon photoreceptor injury, mmp-9 is induced in Müller glia and Müller 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 survival of the regenerated cones. At all time-points studied, the levels of tnf-α are significantly elevated in mutant retinas.Anti-inflammatory treatment in mutants rescues the defects in cone survival. These data provide a link between injury-induced inflammation in the vertebrate CNS, Mmp-9 function during neuronal regeneration and the requirement of Mmp-9 for the survival of regenerated cones.
51Brain injury activates complex inflammatory signals in dying neurons, surviving neurons, and 52 glia. Here, we establish that inflammation regulates the regeneration of photoreceptors in the 53 zebrafish retina and determine the cellular expression and function of the inflammatory 54 protease, matrix metalloproteinase 9 (Mmp-9), during this regenerative neurogenesis. Animals 55 of either sex were used in this study. Following photoreceptor ablation, anti-inflammatory 56 treatment suppresses the number of injury-induced progenitors and regenerated 57 photoreceptors. Upon photoreceptor injury, mmp-9 is induced in Müller glia, the intrinsic retinal 58 stem cell, and Müller glia-derived photoreceptor progenitors. Deleting mmp-9 results in over 59 production of injury-induced progenitors and regenerated photoreceptors, but over time the 60 absence of Mmp-9 compromises the maturation and survival of the regenerated cones. Anti-61 inflammatory treatment in mutants rescues the defects in cone maturation and survival. These 62 data provide a link between injury-induced inflammation in the vertebrate CNS, Mmp-9 function 63 during photoreceptor regeneration and the requirement of Mmp-9 for the survival of regenerated 64 cones. 65 66 67 68 69 70 71 72 73 74 75 3 Significance Statement 76 77 The innate immune system is activated by neuronal death, and recent studies demonstrate that 78 in zebrafish neuroinflammation is required for neuronal regeneration. The roles of inflammatory 79 cytokines are being investigated, however, the function of the inflammatory protease, matrix 80 metalloprotease Mmp-9, in neuronal regeneration is unknown. We show herein that in adult 81 zebrafish retinal inflammation governs the proliferative phase of the stem cell-based 82 regeneration of rod and cone photoreceptors and determine the specific roles for Mmp-9 in 83 photoreceptor regeneration. This study provides the first mechanistic insights into the potential 84 role of Mmp-9 in retinal regeneration and serves to link neuroinflammation, stem cell-based 85 regeneration of photoreceptors and human photoreceptor disease. 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 2013; Zhao et al., 2014). Following a photolytic lesion, dying photoreceptors secrete Tnf-a, to 129 which Müller glia respond by partial dedifferentiation, synthesis of Tnf-a and entry into the cell 130 cycle (Nelson et al., 2013). Mechanical lesions induce the expression of leptin and Il-6 family 131 cytokines in Müller glia and Müller glia-derived progenitors and is required for injury-induced 132 proliferation (Zhao et al., 2014).133 Matrix metalloproteinase 9 (Mmp-9) is a secreted protease that plays a prominent role in 134 tissue development and homeostasis by acting on extracellular molecules, including adhesion 135
Microglia are brain resident macrophages that play vital roles in central nervous system (CNS) development, homeostasis, and pathology. Microglia both remodel synapses and engulf apoptotic cell corpses during development, but whether unique molecular programs regulate these distinct phagocytic functions is unknown. Here we identify a molecularly distinct microglial subset in the synapse rich regions of the zebrafish (Danio rerio) brain. We found that ramified microglia increased in synaptic regions of the midbrain and hindbrain between 7 and 28 days post fertilization. In contrast, microglia in the optic tectum were ameboid and clustered around neurogenic zones. Using single-cell mRNA sequencing combined with metadata from regional bulk sequencing, we identified synaptic-region associated microglia (SAMs) that were highly enriched in the hindbrain and expressed multiple candidate synapse modulating genes, including genes in the complement pathway. In contrast, neurogenic associated microglia (NAMs) were enriched in the optic tectum, had active cathepsin activity, and preferentially engulfed neuronal corpses. These data reveal that molecularly distinct phagocytic programs mediate synaptic remodeling and cell engulfment, and establish the zebrafish hindbrain as a model for investigating microglial-synapse interactions.
Microglia are brain resident macrophages that play vital roles in central nervous system (CNS) development, homeostasis, and pathology. Microglia both remodel synapses and engulf apoptotic cell corpses during development, but whether unique molecular programs regulate these distinct phagocytic functions is unknown. Here we identify a molecularly distinct synapse-associated microglial subset in the zebrafish (Danio rerio). We found that ramified microglia populated synapse-rich regions of the midbrain and hindbrain between 7 and 28 days post fertilization. In contrast, microglia in the optic tectum were ameboid and clustered around neurogenic zones. Using single-cell mRNA sequencing combined with metadata from regional bulk sequencing, we identified synapse-associated microglia (SAMs) that were highly enriched in the hindbrain, expressed known synapse modulating genes as well as novel candidates, and engulfed synaptic proteins. In contrast, neurogenic-associated microglia (NAMs) were enriched in optic tectum, had active cathepsin activity, and preferentially engulfed neuronal corpses. These data yielded a functionally annotated atlas of zebrafish microglia (https://www.annamolofskylab.org/microglia-sequencing). Furthermore, they reveal that molecularly distinct phagocytic programs mediate synaptic remodeling and cell engulfment, and establish zebrafish hindbrain as a model circuit for investigating microglial-synapse interactions.
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