Intrinsic control of early microglia development and its impact on neural cell development

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Origins of many neurodevelopmental disorders such as autism and schizophrenia encompass both genetic and environmental factors. Accumulating evidence indicates that immune response is a key underlying component of both genetic and environmental contributions to these disorders, highlighting the importance of neuroimmune interactions in brain development. Microglia are resident immune cells in the central nervous system and are critical for the homeostasis of adult and aging brains as well as for the pruning of synapses in developing postnatal brains. Microglia appear in early embryonic brains at the time when neurogenesis starts, and undergo a series of changes in gene expression and morphology resulting in temporal and spatial heterogeneity throughout development. Recent studies have addressed whether embryonic microglia influence early neurodevelopmental events by either genetically or chemically ablating microglia or causing systemic maternal immune activation. These studies suggest that early embryonic microglia might have roles in neurogenesis and neuronal migration as well as axon growth and guidance. However, these early roles are not as well understood compared with later developmental roles due to various limitations including: 1) cell ablation cannot address the specific contribution of certain microglia types or states in developing brains, precluding the elucidation of molecular mechanisms, and 2) maternal immune activation not only affects microglia but can also directly impact neural cells. In addition, some of the previous studies show conflicting results on the alteration of neurogenesis in response to microglia ablation. To overcome these limitations, we have developed and analyzed mutant mice in which the zinc finger transcription factor SALL1 is knocked out specifically in microglia. We found by immunostaining and morphology analysis that microglia development is intrinsically perturbed in the absence of SALL1 starting in embryonic brains where neurogenesis and early axon development are underway. In the proposed exploratory research project, we plan to perform single-cell RNA sequencing comparing microglia from Sall1 mutant mice and wild-type controls, and identify the altered microglia subpopulations as well as altered gene expression within each microglia subpopulation. We will next analyze various key aspects early neural development in Sall1 mutant mice and determine whether altered development of microglia impacts these events. By combining the results of these two studies, we expect to develop a valid hypothesis that would explain the molecular underpinnings of early neuroimmune interactions involving diverse microglia populations. In the long term, this project will provide an important positive impact on our understanding of how disrupted microglia development contributes to neurodevelopmental disorders and on subsequent development of novel targeted interventions to treat these disorders.