Figure 5.

Human microglia activation leads to Wnt/β-catenin downregulation and genetic variation in the Wnt pathway associates with preterm infant white matter phenotype. (A) Human primary microglia exposed to LPS showing immunoreactive changes with IBA1 (scale bar = 50 μm); (B) upregulated mRNA expression for COX2 (PTGS2); and (C) the associated decrease in the expression of the gene for β-catenin (CTNNB1). Min to max box and whiskers plots, Student’s t-test, ^**P < 0.01, ^***P < 0.0001, n = 6–9/group. (D) Schematic of the analysis for any association between SNPs in the Wnt pathway and the preterm infant white matter phenotype. Common genetic variation (SNPs) in the WNT gene-set were enriched for variants associated with tractography features when compared to random matched gene-sets, i.e. competitive test, P = 0.037, 1000 permutations, (E, blue inset) and is also associated with white matter probabilistic tractography in preterm infants, compared with the null background, i.e. self-contained test, P = 0.064, 1000 permutations (E, blue inset). (F) The predicted consequences of all of the SNPs found in the top 10 ranked WNT genes shown in Table 1, a total of 42 SNPs. (G) The relationships between these 10 genes significantly associated with the tractography phenotype is reconstructed in a high confidence interaction network specific to the human brain, retrieved from known tissue-specific expression and regulatory data (Greene et al., 2015).