| Description |
The role the innate immune system plays in neuropsychiatric disorders is rapidly becoming illuminated. While functional heterogeneity of innate immune cells has been demonstrated, whether the developmental origin(s) and ontogeny contribute to these diverse functions is not known. A growing body of work centers around the origin(s) and ontogeny of 1 class of innate immune cells, called tissue-resident macrophages. These fully differentiated cells arise from hematopoiesis (development of blood cells) during embryonic development. A subpopulation of tissue-resident macrophages of the brain (i.e., microglia) and adult blood cells transiently express the protein Hoxb8 very early on in differentiation, suggesting that Hoxb8 plays a role in the hematopoietic stem or progenitor cells. Until recently, microglia were thought to be homogeneous in development and function. Recent RNA sequencing of microglia highlights a cell population diverse in function, distribution, and response to injury and disease, which may be a product of their lineage origin and development. What is the biological significance of Hoxb8 expression in a lineage that gives rise to microglia? A loss-of-function mutation in Hoxb8 results in a pathological grooming phenotype in adult mice like that seen in humans with Trichotillomania, an obsessive-compulsive disorder. Dysfunctional Hoxb8 microglia have been suggested to be causative for pathological grooming. This dissertation provides a broad overview of the development of tissue-resident macrophages of the Hoxb8 lineage; explores the ontogeny, functions, and characteristics of Hoxb8 microglia; and establishes a Hoxb8 microglia transplantation mouse model. A distinct ontogeny may provide opportunities for Hoxb8 microglia to develop a set of distinct functions. Functional heterogeneity among microglia offers a preliminary framework to create therapeutic strategies directed at microglia, such as microglial replenishment, to correct the abnormal function of specific subsets of microglia, like Hoxb8 microglia, that appear to be causative in pathological behavior. |
