Establishing microglial funcation and phenotype in the developing retina: looking through a new lens to untavel disease mechanisms

dissertationMicroglia are the resident macrophage of the central nervous system (CNS) and have significant functions in development and disease. However, in both of these contexts, their role is remarkably complex and outcomes on CNS well-being are often contradictory. While they have been implicated in neurodevelopmental and psychiatric disorders as well as neurodegenerative processes, their precise role is still largely elusive. A surge of research over the last decade has greatly improved our understanding of microglial function during development, with a few reports of parallel mechanisms in disease contexts. Improved understanding of homeostatic functions and phenotypes of microglia during development is essential to determining their contribution to neurodevelopmental disorders, but may also shed light on important mechanisms in neurodegeneration. Here, we define microglial transcriptional states and function in the developing retina: a dynamic, isolated, and well-characterized CNS region. We first utilize a genetic depletion strategy and pharmacological inhibition of microglia to determine their impact on retinal development. We find that microglia limit neuronal density by engulfing nonapoptotic retinal ganglion cells. Further, we determine that the complement pathway signals for their removal as complement proteins label a subset of retinal ganglion cells to be phagocytosed and loss of complement receptor results in increased RGC density. To gain additional insight into their phenotype, we profile retinal microglia across iv development. We determine that retinal microglia express canonical brain microglia genes but progress through unique transcriptional states that differ from brain microglia, suggesting microglial phenotype is significantly shaped by the environment. Furthermore, we identify an intriguing transcriptional signature of postnatal retinal microglia that has overlapping features with a subset of brain microglia present in development, aging, and disease, suggesting a common functional state of microglia. Preliminary evidence suggests that some of the same environmental factors and signaling pathways may be involved in driving this unique functional state in the postnatal retina as in disease. Altogether, our work sheds light on microglia function and phenotype by identifying a previously unknown molecular mechanism for neuronal elimination and providing evidence for a unique functional state of microglia that may be linked to important processes such as phagocytosis and lipid metabolism. Therefore, we elucidate microglia-neuron interactions and microglial phenotypes that are important for normal developmental processes but may also reemerge in contexts of disease