Spatially distinct microglia coordinate the response to photoreceptor injury in zebrafish
Microglia exhibit substantial molecular and functional heterogeneity, however, how the local tissue environment influences their responses to neuronal injury remains poorly understood. The zebrafish retina provides a unique opportunity to examine this relationship, because in addition to microglia within the retinal parenchyma, it contains a distinct population that resides within the subretinal…
Microglia, a type of immune cell, display a high degree of diversity both in terms of their molecular characteristics and their functional roles. However, the influence of the local environment on their responses to neuronal injury is not fully understood. Zebrafish retinas present an ideal model for investigating this relationship, as they contain two groups of microglia: one residing in the retinal parenchyma and another in the subretinal space.
This investigation delved into the structure and molecular diversity of retinal microglia in zebrafish, as well as their reaction to targeted photoreceptor damage. The results revealed that microglia populated unique spatial locations and showcased a range of transcriptional states, such as complement-associated, proliferative, and apoc1/apoeb-enriched populations. This suggests that the heterogeneity of microglia is influenced by both the specific tissue context and cellular mechanisms.
Upon sustaining injury, both subretinal and parenchymal microglia swiftly altered their shape and migrated towards the injury site, leading to their concentration within the subretinal space. These microglia then proliferated primarily within this area. By 14 days post-lesion, after photoreceptor regeneration had mostly concluded, the microglial morphology, distribution, and density largely returned to their pre-lesion state.
Notably, the response of retinal microglia to injury was dynamic, whereas the response of microglia in the optic tectum remained relatively unchanged.
To explore the underlying mechanisms of the distinct microglial populations and their injury-induced responses, the study examined microglia in zebrafish lacking the colony stimulating factor 1 receptor a (Csf1ra). In these mutants, parenchymal microglia were significantly diminished, while the number of subretinal microglia remained unchanged.
Despite the comparable photoreceptor death in both csf1ra mutants and wild-type animals following photolytic injury, the proliferation of microglia in csf1ra mutants was severely hampered, and the usual redistribution of parenchymal microglia was not restored. These findings illuminate the specific spatial and molecular attributes of retinal microglia and underscore the role of Csf1ra signaling in regulating microglial maintenance and injury-induced dynamics during photoreceptor regeneration.
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