Large-scale death of retinal astrocytes during normal development mediated by microglia

Abstract

Naturally-occurring cell death is a fundamental developmental mechanism for regulating cell numbers and sculpting developing organs. This is particularly true in the central nervous system, where large numbers of neurons and oligodendrocytes are eliminated via apoptosis during normal development. Given the profound impact of death upon these two major cell populations, it is surprising that developmental death of another major cell type -the astrocyte -has rarely been studied. It is presently unclear whether astrocytes are subject to significant amounts of developmental death, or how it occurs. Here we address these questions using mouse retinal astrocytes as our model system. We show that the total number of retinal astrocytes declines by over 3-fold during a death period spanning postnatal days 5-14. Surprisingly, these astrocytes do not die by apoptosis, the canonical mechanism underlying the vast majority of developmental cell death. Instead, we find that microglia kill and engulf astrocytes to mediate their developmental removal. Genetic ablation of microglia inhibits astrocyte death, leading to a larger astrocyte population size at the end of the death period. However, astrocyte death is not completely blocked in the absence of microglia, apparently due to the ability of astrocytes to engulf each other. Nevertheless, mice lacking microglia showed significant anatomical changes to the retinal astrocyte network, with functional consequences for the astrocyte-associated vasculature leading to retinal hemorrhage. These results establish a novel modality for naturally-occurring cell death, and demonstrate its importance for formation and integrity of the retinal gliovascular network.

Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development

“…However, the majority of the LT staining in csf1r DM radial glia do not appear as speckles but rather as larger lysosomes (Figure 3d, Movie S5). These lysosomes appear in structures that look like phagolysosomes, suggesting radial glia of csf1r DM larvae are phagocytic, but do not retain LT+ speckles in tremendous amounts like we observed in hexb mutants (Puñal et al, 2019) (Movie S5, Figure 3b-d). In all, we show that loss of Hexb activity early in embryonic development results in the persistence of enlarged lysosomal speckles in RG fibers, likely independent of microglia.…”

“…We did however find increased volume of LT staining in RG of csf1r DM larvae, but these appear different from the LT+ speckles observed in hexb mutants, as they are larger in size and located in phagolysosome‐like structures. Since radial glia or astrocytes may take over phagocytic functions usually performed by microglia, these large LT+ lysosomes could be the result of phagocytic activity of radial glia in the absence of microglia in csf1r DM larvae (Puñal et al, ). Importantly, RG in vertebrates are neuronal stem cells, and are thought to produce most neurons, but also astrocytes and oligodendrocytes (Doetsch, ).…”

Social reprogramming in ants induces longevity-associated glia remodeling

“…In mammals, glia composition and properties display developmental and age-related dynamics (44,55,56) including a shift to a more neuroprotective function as the brain ages (57), and restoration of the phagocytic function of microglia in aged mice improves their cognitive performance (58). In Drosophila, glia are thought to play a role in regulating health and life span (43), and ensheathing glia from aged individuals are less effective in clearing accumulated neuronal debris (41), suggesting that declining ensheathing glia might be a cause rather than a consequence of aging.…”