Origin, Distribution and Functions of Neural Tube Microglia in the Immunoprivileged Central Nervous System

Authors

• C Liu
• Y Mukouyama

Abstract

Pathogenesis of neurodegenerative diseases has been attributed to abnormal behavior of microglia, the resident innate immune cells in the central nervous system (CNS). Adult microglia emerge from progenitor cells during embryogenesis. Despite their embryonic origin, most studies are centered on adult microglia, and little is known about their developmental course as well as the contribution of the fetal programming of microglia in adult diseases. In this study, we have identified two populations of embryonic microglia with a gene signature similar to that is found in adult microglia. These embryonic microglia appear in the neural tube simultaneously at E10.5, yet exhibiting different cellular and spatial properties: the F4/80+ microglia within the neural tube, and the LYVE1+/F4/80+ microglia located at the interface of neural tube. This pattern of microglial distribution persists throughout fetal stages and adulthood. These cells are critical for neural tube development as genetic depletion of embryonic microglia results in neuronal and structural defects in the developing brain. Notably, the heterogeneous populations of embryonic microglia derive from a homogenous progenitor population in the yolk sac. This observation prompted us to explore what controls the unique patterning of embryonic microglia in the CNS tissues. Among the candidate genes from a comprehensive gene expression profiling of these embryonic microglia using RNA-seq analysis, we focused on neuronal progenitors-derived canonical Wnt signaling because Wnt receptors are differentially expressed between the two populations of microglia. We are currently examining what happens to the patterning of embryonic microglia distribution and neuronal development in the mutants lacking Wnt/ß-catenin signaling in microglia. Our work demonstrates the developmental characteristics and physiological significance of embryonic microglia. The clinical relevance of fetal microglia to adult CNS pathological conditions will be addressed in future studies.

Scientific Focus Area: Developmental Biology

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