New findings suggest the human brain may function as two brains in one, with the forebrain and hindbrain tracing back to distinct embryonic origins and following separate developmental programs.
For years, biologists believed the brain emerged from a single pool of progenitor cells. According to research published Friday in Nature Neuroscience, scientists now report that the brain’s front and back begin from entirely different progenitor populations and do not intermingle during early development.
“We’ve shown for the first time that the front of the brain arises from a totally different progenitor cell than the back of the brain,” said Kyle Loh, an associate professor of developmental biology at Stanford Medicine and senior author of the study, in a statement. He said the discovery enables researchers to generate hindbrain neurons in the lab and examine their roles.
Two brains in one traced to early embryonic stages
The forebrain underpins language, awareness and abstract reasoning. The hindbrain, which includes the brain stem, governs core automatic functions such as breathing, sleep regulation, heart rate and hunger, and it coordinates muscles used in speech and swallowing.
Despite these crucial functions, growing human hindbrain neurons in vitro has been a persistent challenge, complicating efforts to investigate disorders that damage them, including spinal muscular atrophy and amyotrophic lateral sclerosis. Researchers mapped the divergence to gastrulation, a formative point in embryogenesis when the body plan begins to take shape.
In mouse embryos, they identified two non-overlapping progenitor pools: cells expressing the gene Otx2 that give rise to the forebrain and midbrain, and cells expressing Gbx2 that produce the hindbrain. The team also analyzed chromatin states, the three-dimensional packaging of DNA that influences gene accessibility.
They found distinct chromatin configurations in the two progenitor types, indicating early commitment to separate developmental trajectories. “Previous attempts to make hindbrain neurons likely tried to coax forebrain and midbrain progenitors into hindbrain cells, which our study shows is not possible,” said graduate student and co-first author Rayyan Jokhai.
Lab-grown hindbrain neurons and evolutionary clues
With the developmental split defined, the researchers directed human pluripotent stem cells to become functional hindbrain motor neurons in vitro for the first time. The resulting cells displayed electrical properties and protein markers characteristic of regions that govern facial and swallowing muscles.
Looking across species, the team reported evidence of a similar two-part pattern in chickens, zebrafish and acorn worms, which share a distant ancestor with humans. Jellyfish, which diverged hundreds of millions of years ago, possess two nervous systems positioned at opposite ends of the body.
“Our research suggests that evolution took two existing neural systems and pushed them together spatially,” Loh said. He added that a unified organ might be more efficient, but development appears to preserve an ancient, two-piece blueprint.
Implications for ALS and brain stem disorders
The ability to grow hindbrain neurons offers a new avenue to study conditions that affect the brain stem, including spinal muscular atrophy and ALS. Because brain stem tissue cannot be taken from living patients, laboratory models are essential to understand how these diseases harm neurons and to test potential therapies.
The researchers plan to probe the developmental origins of the spinal cord and examine how SMA and ALS disrupt hindbrain neuron function. “Now we have a model to better understand these devastating diseases, and work toward regenerative therapies for them,” Jokhai said.
Previous work on Ohio State University research and disclosure practices has underscored how institutional oversight can shape the path of biomedical innovation. This new study adds to a growing body of research that could eventually inform clinical approaches for neurodegenerative diseases.