Abstract
In the developing cortex, postmigratory neurons accumulate in the cortical plate (CP) to properly differentiate consolidating subtype identities. Microglia, despite their extensive surveying activity, temporarily disappear from the midembryonic CP. However, the mechanism and significance of this absence are unknown. Here, we show that microglia bidirectionally migrate via attraction by CXCL12 released from the meninges and subventricular zone and thereby exit the midembryonic CP. Upon nonphysiological excessive exposure to microglia in vivo or in vitro, young postmigratory and in vitro-grown CP neurons showed abnormal differentiation with disturbed expression of the subtype-associated transcription factors and genes implicated in functional neuronal maturation. Notably, this effect is primarily attributed to interleukin 6 and type I interferon secreted by microglia. These results suggest that “sanctuarization” from microglia in the midembryonic CP is required for neurons to appropriately fine-tune the expression of molecules needed for proper differentiation, thus securing the establishment of functional cortical circuit.
Highlights
In the developing cortex, postmigratory neurons accumulate in the cortical plate (CP) to properly differentiate consolidating subtype identities
Coimmunostaining for P2RY12 and CD20622 on E15 revealed that P2RY12+ microglia existed beneath the meninges, which contained CD206+ macrophages (Fig. 1e), suggesting that microglia that migrated toward the meninges accumulated in the marginal zone (MZ)
To test whether microglia are attracted by the meninges, we performed live monitoring in cortical slices freed from the meninges
Summary
Postmigratory neurons accumulate in the cortical plate (CP) to properly differentiate consolidating subtype identities. Embryonic pallial microglia play multiple roles in neurogenesis, e.g., by phagocytotically regulating the number of Tbr2+ neural progenitors[9,10] and inducing neural stem-like cells to differentiate into Tbr2+ intermediate progenitors[11,12] These microglial functions are exerted in the regions in which they exist and are needed. Intrapallial microglial distribution is initially homogenous until E14, but these cells temporarily disappear from the cortical plate (CP) from E15 to E16 and show preferences for colonizing the ventricular zone (VZ), subventricular zone (SVZ), and intermediate zone (IZ)[9,14] Considering their contribution to the survival of layer 5 (L5) neurons in the postnatal brain[15], the fundamental question as to why they need to transiently exit the midembryonic CP is raised. In light of these observations, we hypothesized that microglia transiently disappear from the midembryonic CP to avoid disturbing neuronal functional differentiation, and we performed experiments to artificially expose CP neurons to excessive microglia
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