Lymphatics help 'seed' early brain cells in zebrafish

During the embryonic stage of brain development, some neurons and synapses are well formed and connected, but others are not, causing some parts and parts to be discarded. This leaves dead or dying cells and requires the central nervous system to employ some kind of cleaning crew.

Microglial cells take up the challenge, “swallow” waste, and are therefore essential for brain development. However, scientists don’t have a full understanding of how they populate the brain. A recent paper in Nature Neuroscience by University of Notre Dame biologist Cody J. Smith shows how lymphatics – which remove waste from other parts of the body – are also linked to microglia and brain development in zebrafish.

“Microglia, we know, are born outside the brain but somehow have to enter the brain during development, which is called colonization,” said Smith, Elizabeth and Michael Gallagher Associate Professor in the Department of Biological Sciences. “We know that in humans this colonization is present at least at four weeks’ gestation, and we carried out this study with the idea of ​​how we could find pioneer microglia, and find interactions between lymphatics and microglia development.”

In studies of mice and zebrafish, scientists have learned that microglia precursors form in the yolk sac, but they suspect there is another source of these precursors. Using time-lapse imaging, researchers in Smith’s lab showed that microglia-like cells, which express a gene called mrc1a+, begin to populate the zebrafish brain within a day of brain formation. This is much earlier than expected.

More imaging revealed precursor cells containing the mrc1a+ gene migrating from the lymphatics surrounding the brain. When the researchers disrupted the lymphatic cells, they saw a reduced number of microglia precursor cells.

“We found that if we disrupt the lymphatics, we disrupt microglia colonization,” said Smith, who is affiliated with the Notre Dame Center for Stem Cells and Regenerative Medicine.

The team also noticed that the precursor cells that require lymphatics are cells that respond when the developing brain undergoes a developmental injury.

While Smith is pleased with the findings, with his lab’s overall focus on how the nervous system is built, he also appreciates that this type of basic research helps create a blueprint that allows other researchers to understand why defects occur and how to fix them.

Also, Smith was encouraged by how the discovery was made. Researchers had set out to discover what allows microglial cells to respond to injury, but they noticed during one last control test that there were more microglial cells than they had seen before. So, the lab investigated that part further.

“Understanding the basic science is very important, but this is an example where we really try to chase one thing and end up on something completely different,” said Smith.

This research was supported by the Alfred P. Sloan Foundation, the National Institutes of Health, and the Indiana Brain and Spinal Injury Research program with the Indiana State Council of Health.

In addition to Smith, other authors include former doctoral student Lauren A. Green, postdoctoral researcher Dana F. DeSantis, doctoral student Camden A. Hoover and former undergraduate student Michael R. O’Dea, all in Smith’s laboratory.

Reference:

1. Lauren A. Green, Michael R. O’Dea, Camden A. Hoover, Dana F. DeSantis, Cody J. Smith. The embryonic zebrafish brain was seeded by a lymphatic-dependent mrc1+ microglia precursor population. Natural Neuroscience, 2022; 25 (7): 849 DOI: 10.1038/s41593-022-01091-9

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