Abstract
Despite a growing appreciation for microglial influences on the developing brain, the responsiveness of microglia to insults during gestation remains less well characterized, especially in the embryo when microglia themselves are still maturing. Here, we asked if fetal microglia could coordinate an innate immune response to an exogenous insult. Using time-lapse imaging, we showed that hypothalamic microglia actively surveyed their environment by near-constant "touching" of radial glia projections. However, following an insult (i.e., IUE or AAV transduction), this seemingly passive touching became more intimate and long lasting, ultimately resulting in the retraction of radial glial projections and degeneration into small pieces. Mechanistically, the TAM receptors MERTK and AXL were upregulated in microglia following the insult, and Annexin V treatment inhibited radial glia breakage and engulfment by microglia. These data demonstrate a remarkable responsiveness of embryonic microglia to insults during gestation, a critical window for neurodevelopment.
Highlights
Microglia are the resident phagocytic immune cells of the central nervous system (CNS)
Microglia Interact with Hypothalamic Radial Glia during Embryogenesis Microglia colonize the brain during embryonic development, with some microglia positioning themselves alongside radial glial cell (RGC), the multipotent progenitor cells that give rise to the neurons, oligodendrocytes, astrocytes, and tanycytes found in the hypothalamus (Marsters et al, 2016; Rosin et al, 2018)
In the embryonic day (E) 15.5 hypothalamus, radial glia express both glutamate aspartate transporter (GLAST; Figures 1A–1D0) and glial fibrillary acidic protein (GFAP; Figures 1E–1F0), GLAST is more robustly expressed in the projections than GFAP at E15.5
Summary
Microglia are the resident phagocytic immune cells of the central nervous system (CNS). In the embryonic cortex, microglia are involved in neural progenitor maintenance (Antony et al, 2011) and the termination of neurogenesis by engulfing unnecessary cortical progenitors (Cunningham et al, 2013). Microglia influence both dendritic spine formation (Miyamoto et al, 2016) and synaptic pruning (Paolicelli et al, 2011; Schafer et al, 2012; Tremblay et al, 2010), which together can have a significant impact on neuronal connectivity. A growing body of literature describes microglia influencing developmental programs of the embryonic and postnatal CNS; the responsiveness and coordination of an innate immune response to an exogenous insult during gestation, an important role in the adult brain, is less well characterized
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