Microglia shape corpus callosum axon tract fasciculation: functional impact of prenatal inflammation

Abstract

Microglia colonise the brain parenchyma at early stages of development and accumulate in specific regions where they participate in cell death, angiogenesis, neurogenesis and synapse elimination. A recurring feature of embryonic microglial is their association with developing axon tracts, which, together with in vitro data, supports the idea of a physiological role for microglia in neurite development. Yet the demonstration of this role of microglia is lacking. Here, we have studied the consequences of microglial dysfunction on the formation of the corpus callosum, the largest commissure of the mammalian brain, which shows consistent microglial accumulation during development. We studied two models of microglial dysfunction: the loss-of-function of DAP12, a key microglial-specific signalling molecule, and a model of maternal inflammation by peritoneal injection of lipopolysaccharide at embryonic day (E)15.5. We also took advantage of the Pu.1(-/-) mouse line, which is devoid of microglia. We performed transcriptional profiling of maternally inflamed and Dap12-mutant microglia at E17.5. The two treatments principally down-regulated genes involved in nervous system development and function, particularly in neurite formation. We then analysed the developmental consequences of these microglial dysfunctions on the formation of the corpus callosum. We show that all three models of altered microglial activity resulted in the defasciculation of dorsal callosal axons. Our study demonstrates that microglia display a neurite-development-promoting function and are genuine actors of corpus callosum development. It further shows that microglial activation impinges on this function, thereby revealing that prenatal inflammation impairs neuronal development through a loss of trophic support.

The Indispensable Roles of Microglia and Astrocytes during Brain Development

“…In various brain regions in different species such as rodents (Ashwell et al, 1989; Pont-Lezica et al, 2014), birds (Cuadros et al, 1993), zebrafish (Herbomel et al, 2001), cats (Innocenti et al, 1983) and humans (Rezaie et al, 1999; Verney et al, 2010), microglia are found to be closely associated with developing axonal tracks. For example, in rodents microglia were found in developing marginal zones (MZ) that contain developing axon fascicles (Cuadros et al, 1993; Soria and Fairén, 2000), the subpallium (Squarzoni et al, 2014), the corpus callosum (Pont-Lezica et al, 2014) and the hippocampal commissure (Dalmau et al, 1997a, 1998).…”

“…For example, in rodents microglia were found in developing marginal zones (MZ) that contain developing axon fascicles (Cuadros et al, 1993; Soria and Fairén, 2000), the subpallium (Squarzoni et al, 2014), the corpus callosum (Pont-Lezica et al, 2014) and the hippocampal commissure (Dalmau et al, 1997a, 1998). Microglia associated with white matter acquire a distinct morphology which differs from the microglia located in gray matter.…”

Microglia: Architects of the Developing Nervous System

“…Depletion or activation of microglia, as well as genetic deletion of CX3CR1 or DAP12, resulted in premature entry and abnormal distribution of Lhx6 -expressing interneurons in the embryonic cortical plate and a 10% decrease in a subset of interneurons in the postnatal cortex. In another study, outgrowth and fasciculation of axons within corpus callosum were assessed in embryonic PU.1 −/− , DAP12 −/− , or LPS-treated mice [66]. Gene expression profiles at E17.5 revealed a down-regulation of genes related to neuritogenesis in DAP12 −/− and LPS-treated mice, which were accompanied by a significant increase in defasciculated axon tracts in the corpus callosum of PU.1 −/− , DAP12 −/− , and LPS-treated mice.…”

Role of microglia in fungal infections of the central nervous system

“…40,41 These findings were later validated by showing that microglia's transcriptomic activity is unambiguously different to those of peripheral monocytederived macrophages, regardless of their anatomical origin. 18 Likewise, numerous studies have demonstrated microglia's own biological identity including the regulation of synaptic pruning and plasticity, [42][43][44] the spatial distribution of axonal projections, 45,46 and neuronal homeostasis and survival. 47,48 Alternatively, a current hypothesis proposes that microglial reactivity may be stimulated by damaged neurons with deficient signaling, the presence of circulatory plasma molecules in the CNS due to the BBB disruption, and peripheral leukocyte signaling mediated by cytokines after interactions with microbes or their antigens.…”