Large-scale death of retinal astrocytes during normal development is non-apoptotic and implemented 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 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 developmental death, and if so, 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 engulf astrocytes during the death period to promote 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 the formation and integrity of the retinal gliovascular network.

Astrocytes and microglia play orchestrated roles and respect phagocytic territories during neuronal corpse removal in vivo

“…Microglia are considered the primary brain resident phagocytes, although astrocytes have also been shown to exhibit phagocytic functions in vitro, during development, and after injury (16,34,(40)(41)(42)(43). It is not known how these cells coordinate their functions and whether they have specialized roles during corpse removal in homeostatic and pathological conditions.…”

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.…”

Neuronal Dystroglycan regulates postnatal development of CCK/cannabinoid receptor-1 interneurons

“…This suggests that canonical apoptosis is not responsible for the loss of CCK+ INs in Dag1 cKO mice. It is possible that CCK+ INs are eliminated in a Bax -independent manner, similar to some populations of Cajal-Retzius cells in the cortex and astrocytes in the developing retina (Ledonne et al, 2016; Punal et al, 2019).…”