The embryonic zebrafish brain is seeded by a lymphatic-dependent population of mrc1⁺ microglia precursors

Area of Science:

• Neuroscience
• Developmental Biology
• Immunology

Background:

• Microglia, the central nervous system's resident macrophages, are crucial for brain development.
• The origin and earliest seeding of microglia in the developing brain remain incompletely understood.
• While microglia are present by 4 weeks gestation in humans, their initial precursors are not fully characterized.

Purpose of the Study:

• To identify and characterize the earliest microglia precursors that colonize the embryonic brain.
• To investigate the developmental origins and dependencies of these nascent microglia.
• To explore the role of lymphatic vasculature in early brain colonization by microglia.

Main Methods:

• Time-lapse imaging in zebrafish to observe microglia precursor dynamics.
• Single-cell RNA-sequencing of embryonic mouse and human brain cells.
• Analysis of microglia precursor dependence on lymphatic vasculature and yolk sac-derived microglia (pu1+).

Main Results:

• Discovery of a novel mrc1a+ microglia precursor population that seeds the zebrafish brain before previously identified microglia.
• These mrc1a+ precursors are dependent on surrounding lymphatic vasculature and independent of pu1+ yolk sac-derived microglia.
• Mrc1+ microglia were identified in embryonic mouse and human brain datasets.
• The mrc1a+ microglia precursors showed preferential expansion during developmental pathophysiological states in zebrafish.

Conclusions:

• Identification of a distinct, early-arriving microglia precursor population (mrc1a+) in the embryonic brain.
• Demonstration of the critical role of lymphatic vasculature in the colonization of the brain by these early microglia precursors.
• These findings provide new insights into the complex origins and developmental regulation of microglia in the central nervous system.