Complex invasion pattern of the cerebral cortex bymicroglial cells during development of the mouse embryo

Abstract

Microglia are the immune cells of the central nervous system. They are suspected to play important roles in adult synaptogenesis and in the development of the neuronal network. Microglial cells originate from progenitors in the yolk sac. Although it was suggested that they invade the cortex at early developmental stages in the embryo, their invasion pattern remains largely unknown. To address this issue we analyzed the pattern of cortical invasion by microglial cells in mouse embryos at the onset of neuronal cell migration using in vivo immunohistochemistry and ex vivo time-lapse analysis of microglial cells. Microglial cells begin to invade the cortex at 11.5 days of embryonic age (E11.5). They first accumulate at the pial surface and within the lateral ventricles, after which they spread throughout the cortical wall, avoiding the cortical plate region in later embryonic ages. The invasion of the cortical parenchyma occurs in different phases. First, there is a gradual increase of microglial cells between E10.5 and E14.5. From E14.5 to E15.5 there is a rapid phase with a massive increase in microglia, followed by a slow phase again from E15.5 until E17.5. At early stages, many peripheral microglia are actively proliferating before entering the parenchyma. Remarkably, activated microglia accumulate in the choroid plexus primordium, where they are in the proximity of dying cells. Time-lapse analysis shows that embryonic microglia are highly dynamic cells.

Neural progenitor cells orchestrate microglia migration and positioning into the developing cortex

“…1a,b), at E14.5, E16.5 and E18.5 such cells were preferentially clustered into the VZ/SVZ of the cerebral cortex ( Supplementary Fig. 1a-c) 15 . Because microglia cell number significantly increased along neurogenesis in cortical and subcortical areas (Fig.…”

“…9) to promote the development of Cajal-Retzius cells 49 -are not affected in our mutant mice, thus suggesting that they might per se contribute to attract circulating microglia. Owing to the fact that B20% of the mid-end gestational cortical microglia is actively proliferating 15 , we cannot exclude that cell proliferation represents a rescue mechanism aimed at balancing microglia depletion occurring as a consequence of Cxcl12 reduction. Apart from the existence of additional sources of Cxcl12 in the developing brain, we cannot rule out the possibility of the existence in the developing brain of microglia progenitors, able to proliferate in order to replenish the microglia cell pool as occurs in pathological conditions determining microglia depletion in the adult brain 50 .…”

“…Microglia are immune-relevant cells of the central nervous system that are generated within the yolk sac at embryonic day (E) 8 and colonize the forebrain just before the onset of neurogenesis 11,12 . Once seeded into the cerebral cortex, microglia first accumulate at the pail surface and into the choroid plexus and then penetrate the cortical wall, clustering into a restricted laminar band that overlaps the cortical VZ/SVZ [13][14][15] . To date, little is known about mechanisms regulating microglia migration, recruitment and positioning into the developing cortex.…”

Serotonin Modulates Developmental Microglia via 5-HT2B Receptors: Potential Implication during Synaptic Refinement of Retinogeniculate Projections

“…Similarly, electrophysiological studies in mouse cortex have revealed that the population of early postnatal microglia presents a transient outward rectifying current above -30mV mediated by Kv1.3 potassium channels, similar to activated microglia, however, these postnatal microglia do not express other known activation markers like Mac2 or MHCII 12 . Additionally, these microglial cells also express a panel of specific markers including purinergic receptors 10,12 . The mouse retinogeniculate system is a classic model for studying developmental synapse elimination.…”

Cellules microgliales et développement du système nerveux central chez l’embryon

“…De telles études ont pu être mises en oeuvre grâce à l'utilisation d'anticorps spécifiques dirigés contre des protéines exprimées par les cellules microgliales, et surtout grâce à la production de souris exprimant la eGFP (enhanced green fluorescent protein, une protéine fluorescente) dans les cellules microgliales (souris CX 3 CR1eGFP) [9]. Chez la souris, les cellules microgliales envahissent la moelle épi-nière (ME) et le cerveau au même âge embryonnaire [10,11]. Des macrophages immatures sont observés autour du parenchyme neural vers le 9,5 e -10,5 e jour après la fertilisation (E9,5-E10,5), qui forment probablement un réservoir de cellules microgliales.…”