Differential impact of Dicer deficiency on microglia of the developing and adult brain (Agilent miRNA microarrays). Mus musculus

Microglia seed the embryonic neuro-epithelium, expand and actively sculpt neuronal circuits in the developing CNS, but eventually adopt relative quiescence and ramified morphology in the adult. Here we probed the impact of post-transcriptional control by microRNAs (miRNAs) on microglial performance during development and adulthood by generating mice lacking microglial dicer expression at these distinct stages. RNA seq of conditional dicer ablation in adult microglia revealed that miRNAs were required to limit microglial responses to challenge but had only minor changes on non-challenged microglia. Specifically, following peripheral endotoxin exposure of the animals (LPS), Dicer-deficient microglia either from total brain or hippocampus overexpressed pro-inflammatory cytokines and as a result compromised hippocampal neuronal functions. In contrast, prenatal ablation resulted in spontaneous microglia activation and revealed Dicer involvement in DNA repair and preservation of genome integrity. Overall, our study shows miRNA and Dicer regulation of inflammatory response either following challenge in the adult or spontaneously in the newborn microglia. Moreover, Dicer is required for preservation of microglia DNA integrity required for their proliferation, longevity and radioresistance. Overall design: Adult Microglia (defined as CD45intCD11b+F4/80+Ly6C-Ly6G- cells, n=2, each replicte is a pool of 4-6 mice), Colon MFs (defined as CD45+CD11b+CD11c+CD64+Ly6C-, n=2, each replicate is a pool of 4-6 mice), and Liver MFs (KCs) (defined as CD45+CD11b+F4/80+CD64+MHCII+, n=2, each replicate is a pool of 4-6 mice) were sorted from 6-8 weeks old WT mice. miRNA microarray profiling was performed on the populations above in order to identify miRNAs enriched in steady state adult microglia.