Analysis of the biological roles of the vertebrate-specific, ovarian tumor (OTU) domain Fam105a protein

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Inflammatory signals emanating from the brain or distant organs can have considerable impacts on the developing and adult nervous system. For example, in rodents and primates, severe intestinal infections can activate the maternal immune system and cause behavioral and brain abnormalities in the resulting offspring. Further underscoring the complexity of neuroimmune crosstalk: both anti-viral responses and normal neuronal differentiation increase expression of immune signaling molecules called type I interferons, and some IFNs themselves can halt or impair neural stem cell proliferation. Mitochondria play roles in cell metabolism, responses to infectious agents and in immune and nervous system function. Cells regulate mitochondrial numbers by mitophagy. Some immune cells, such as for example, macrophages, use mitophagy to shift their metabolism and thereby their inflammatory state. Macrophages provide an ideal system for analyzing the interplay between mitophagy, cell state, inflammation and responses to infections. Macrophages can be classified into two groups: Pro-inflammatory, classically activated (M1) macrophages help eliminate infections. Atypically activated (M2) macrophages are judged anti-inflammatory and promote tissue repair. Induction of mitophagy and a shift towards glycolysis occurs during pro-inflammatory M1 macrophage activation. Recently we obtained evidence that the Ovarian Tumor (OTU) domain protein Fam105a/OtulinL may regulate mammalian mitophagy and be involved in immune and directly or indirectly nervous system homeostasis. FAM105A interacts with proteins known to regulate mitophagy. Moreover, we observed that mice lacking Fam105a show evidence of immune and nervous system dysfunction. Thus, we hypothesize that Fam105a regulates mammalian mitophagy and normally dampens innate immune activation. In its absence, nervous system dysfunction arises due to primary effects of disrupted mitochondrial dynamics in neurons or secondary consequences of (auto)-inflammation occurring in other regions of the body. To address this we will analyze the role of Fam105a in mitochondrial dynamics in bone marrow-derived macrophages (BMDMs) from mice lacking Fam105a with Drs. Angus McQuibban (UofT) and Andrea Jurisicova (LTRI).We will also analyze the roles of Fam105a in induction of M1/M2 states in macrophages and in anti-viral responses with Dr. John Brumell (HSC). We will determine whether losing Fam105a in nerves themselves causes behavioural abnormalities or whether inflammation in other regions of the body contributes to brain and behavioural abnormalities. These analyses will provide a new avenue for understanding the neuroimmune axis and the interactions between genetics, environmental challenges (i.e. infectious agents) and physiologic state (e.g. pregnancy) that shape mammalian neurodevelopment and behavior.