Thursday, December 26, 2024
12/26/2024
ABSTRACT Microglia are the resident immune cells of the Central Nervous System (CNS). They are positioned at the center of brain development and function by playing crucial roles in neuronal network architecture and homeostatic surveillance. Unlike other CNS-resident cells, microglia originate outside the brain, specifically in the embryonic yolk sac (YS). Before microglia can serve their crucial functions, they must first migrate to and infiltrate the developing brain. The cellular and molecular dynamics governing this process are not fully understood, and what we do know is based on YS- derived microglia. However, cre/lox fate mapping studies only map ~30% of all mouse microglia to the YS. This suggests additional sources and populations of microglia could exist. This has been confirmed in zebrafish, where microglia have additional, non-YS origins. The discovery of additional microglia populations leaves us with even less understanding of how microglial precursors seed the brain, especially given that what we do know is from YS-derived microglia only. To begin to fill this critical gap, we investigated the microglia that seed the embryonic brain. Because microglia seeding the brain is a highly dynamic process, we utilized timelapse imaging in zebrafish to watch the cells live. We identified an undescribed cell in the brain that expresses canonical microglia markers, clears debris, and expands in injury. These microglia-like cells are labeled with Mannose Receptor C, type 1a (mrc1a) and colonize the brain earlier than known microglia precursors. mrc1a+ microglia are dependent on the mrc1a+ lymphatic vessels sitting just outside the CNS boundary. These mrc1a+ cells are located within the brain parenchyma and do not associate with vessels or the brain-border, suggesting they’re not macrophages, perivascular cells, or brain lymphatic endothelial cells. Despite our discovery of this early-infiltrating population, the dynamics of how this mrc1a+ population colonizes the brain and expands as microglia are unknown. The implication of mrc1a+ brain-border lymphatics in these processes is also undetermined. The goal of the proposed study is to investigate the cellular and molecular characteristics of a novel, mrc1a+ microglia subpopulation as it colonizes, expands, and differentiates in the developing brain. I will accomplish this by using a combination of in vivo imagine, optogenetic tools, and photoactivatable drugs to carry out the following aims: 1. Determine if brain-border lymphatic vessels contribute microglial progenitors to the developing brain. 2. Characterize the molecular profile of mrc1a+ cells as they differentiate into microglia. This work has the potential to impact a broad spectrum of fields including basic neurodevelopmental biology, neurodevelopmental disorder and disease, glial biology, and CNS homeostasis by investigating the fundamental dynamics behind early microglial precursors as they infiltrate the developing brain, expand, and turn on canonical microglia markers.
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