The behavior and functions of embryonic microglia

Abstract

Microglia are the resident immune cells of the central nervous system. Microglial progenitors are generated in the yolk sac during the early embryonic stage. Once microglia enter the brain primordium, these cells colonize the structure through migration and proliferation during brain development. Microglia account for a minor population among the total cells that constitute the developing cortex, but they can associate with many surrounding neural lineage cells by extending their filopodia and through their broad migration capacity. Of note, microglia change their distribution in a stage-dependent manner in the developing brain: microglia are homogenously distributed in the pallium in the early and late embryonic stages, whereas these cells are transiently absent from the cortical plate (CP) from embryonic day (E) 15 to E16 and colonize the ventricular zone (VZ), subventricular zone (SVZ), and intermediate zone (IZ). Previous studies have reported that microglia positioned in the VZ/SVZ/IZ play multiple roles in neural lineage cells, such as regulating neurogenesis, cell survival and neuronal circuit formation. In addition to microglial functions in the zones in which microglia are replenished, these cells indirectly contribute to the proper maturation of post-migratory neurons by exiting the CP during the mid-embryonic stage. Overall, microglial time-dependent distributional changes are necessary to provide particular functions that are required in specific regions. This review summarizes recent advances in the understanding of microglial colonization and multifaceted functions in the developing brain, especially focusing on the embryonic stage, and discuss the molecular mechanisms underlying microglial behaviors.

Keywords: Cortex; Developing brain; Microglia; Neural progenitors; Neurogenesis.

Fig. 1

Distribution and migration of microglia in the developing brain. Embryonic microglia change their distribution in a stage-dependent manner in the developing cerebral wall. Microglia are homogenously distributed in the pallium in the early and late embryonic stages, whereas these cells are transiently absent from the CP from E15 to E16. Microglial migration is regulated by multiple factors, i.e., their morphological characteristics, the structures of surrounding cells, such as blood vessels and fibers of radial glia, and some secretory and cell surface molecules. This figure summarizes these factors which have been suggested to contribute to microglial migration in the embryonic stage. The middle panel shows the mRNA expression level of Cxcl12, which is produced in the meninges and SVZ. As the Cxcl12 mRNA expression is most highly expressed in the SVZ at E14, microglia in the IZ might be able to migrate toward the inner region. On the other hand, microglia positioned in the CP are also attracted toward the meninges, thereby accumulating in the MZ. CP cortical plate, IZ intermediate zone, MMPs metalloproteinases, MZ marginal zone, PP pre-plate, SVZ subventricular zone, VZ ventricular zone

Fig. 2

Excessive microglia disturb the differentiation and maturation of post-migratory neurons in the CP. Microglia transiently exit the CP from E15 to E16. If microglia are inadvertently positioned in the CP, these cells would disturb the expression properties of subtype-associated transcription factors in post-migratory neurons by inducing a reduction of the expression of deep layer (DL) marker genes and an increase of typical upper layer (UL) marker genes. Moreover, IL-6 and IFN-I released from microglia have been identified as two important mediators which participate in the destabilization of the expression of neuronal subtype-associated genes. Thus, the developing cortex might expel microglia from the mid-embryonic CP to appropriately fine-tune the expression of molecules needed for proper differentiation of post-migratory neurons to secure the establishment of functional cortical circuit. CP cortical plate, IFNAR1 interferon alpha/beta receptor, IFN-I type I interferon, IL-6 interleukin-6, IL6R interleukin 6 receptor, IZ intermediate zone, L layer, MZ marginal zone, SVZ subventricular zone, VZ ventricular zone