For decades, the scientific consensus held that a single type of starter cell was responsible for generating the entire brain. However, new experiments published in Nature Neuroscience challenge this fundamental assumption, providing evidence that two distinct types of progenitor cells are required to build the complex organ.
The study indicates that one lineage of precursor cells gives rise to the hindbrain, which governs vital autonomic functions such as breathing and heart rate. A second progenitor type generates both the forebrain, associated with higher-order cognitive processes like reasoning and planning, and the midbrain.
“The brain is one organ,” explained Kyle Loh, a development biologist at Stanford University in California and co-author of the study. “But it’s built in two different parts that connect and work together.”
To determine whether precursor cells were strictly committed to specific brain regions, Loh and his team examined mouse embryos 7.5 days after conception. Using tissue staining and RNA sequencing, they identified two mutually exclusive clusters of brain progenitors. By tagging cells expressing a back-of-the-brain gene with red fluorescent markers, the researchers tracked their development in mature brains. “The back half of the brain was red, but not the front part,” Loh noted.
The team replicated these findings in human pluripotent stem cells, which can differentiate into nearly any adult tissue type. When exposed to chemical signals intended to create forebrain or midbrain structures, one cell type matured readily. However, when subjected to signals meant to produce hindbrain tissue, these cells failed to progress, suggesting their developmental fate was already locked in.
The researchers also investigated a broad range of species, including monkeys, chickens, zebrafish, and Saccoglossus kowalevskii, a marine invertebrate known as an acorn worm. They discovered the two varieties of brain precursors in every species examined. Loh expressed astonishment at the discovery in acorn worms, noting that the last common ancestor of humans and these invertebrates lived over 500 million years ago, before the formation of the supercontinent Pangaea. Despite this vast evolutionary divide, their embryonic development appears remarkably similar.
While the conclusion that the brain descends from two non-mixing cell populations has not gone entirely unchallenged, the research has received broad praise for a specific methodological breakthrough: an efficient technique for coaxing stem cells into hindbrain motor neurons. These cells control essential movements such as swallowing. This advance could significantly aid research into neurodegenerative conditions affecting these neurons, including amyotrophic lateral sclerosis (ALS), also known as motor neuron disease.
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