Apoptosis at the optic fissure shapes transient retinal myeloid states

Abstract

Microglia and CNS-associated macrophages (CAMs) originate from yolk sac erythromyeloid progenitors, yet the process that mediates their colonization of the mammalian eye and the developmental cues that promote their diversification remain unclear. Here, we identify the optic fissure as the primary entry site for myeloid cells into the embryonic mouse retina. This entry is spatially and temporally coupled with a localized wave of cell death. This apoptotic niche contains colonizing myeloid cells in a transient CD206+ state, and apoptotic burden directly correlates with CD206 expression across development. We find that disrupting apoptotic recognition pathways, specifically Cx3cr1 and Itgam, promotes enrichment of CD206+ cells; likewise, increasing cell death via genetic loss of Atoh7 results in elevated CD206+ population, indicating that impaired clearance and increased death converge on a common outcome within a constrained developmental window. Both CD206+ and CD206- subsets contribute to phagocytosis during optic fissure closure, indicating that CD206 expression does not mark a specialized phagocytic subset. Intriguingly, unlike parenchymal microglia, CD206+ cells are selectively spared from pharmacological CSF1R inhibition, revealing distinct survival requirements within the fissure niche. Together, these findings indicate that localized apoptotic niches encountered during myeloid cell entry influence the initial states and properties of CNS-resident myeloid cells.