Background: Canine gliomas are uniformly fatal primary brain tumors of dogs. We have demonstrated that microglia-derived olfactomedin-like 3 (OLFML3) has myriad pro-tumorigenic roles in glioma. However, its role in neurodevelopment and microglial function must be further defined. Hypothesis/
Objective: To determine whether Olfml3 heterozygous (Olfml3+/−) mice demonstrate alterations in behavior, brain cellular architecture, and/or microglial function. Animals: Male and female C57BL/6N wild-type and Olfml3+/− mice.
Methods: This was a controlled experimental study. Behavioral testing was performed at 4, 6, and 8 weeks of age, followed by necropsy and brain histopathological analysis. Neuron, astrocyte, and microglia cellular density was quantified across multiple brain regions. Ex vivo microglial chemotaxis, phagocytosis and cytokine profiles (n=18 targets) were assessed in 8-week-old mice. Behavioral data were analyzed using mixed effects models. Cellular density was analyzed within sex using t tests. Chemotaxis and phagocytosis were analyzed using two-way analysis of variance and unpaired t tests, respectively. Cytokine profiles were assessed via mixed effect model in limma.
Results: Behavioral performance and brain histopathology were comparable between genotypes in both sexes. Cellular densities did not differ between genotypes or sex. However, microglia from Olfml3+/− females demonstrated increased chemotaxis toward ATP (p = 0.0009) and increased secretion of monocyte chemoattractant protein 1 (MCP-1; p = 0.00196) compared microglia from wild-type female mice. Conclusions and Clinical Importance: Olfml3 haploinsufficiency was associated with sex-specific changes in microglial function, without disrupting normal brain development or gross neurologic function. OLFML3 may play a regulatory role in microglial immune signaling in a sex-dependent manner.
