Recent research challenges a long-held idea about how the brain develops: Rather than coming from a single source, the brain may emerge from two distinct populations of cells, the study suggests.
“The brain appears as a single organ,” said study co-author Kyle Lohassociate professor of developmental biology at Stanford University. “However, we found that the front and back of the brain arise from different sources, which are pushed together to create the appearance of a single organ,” Loh told Live Science in an email.
The results, published in September in the journal Natural neurosciencenot just a challenge established models of how the brain forms but it may also explain why researchers have had difficulty growing certain types of brain cells in the laboratory. Scientists say this work could offer new ways to study diseases that affect the brainstem, the “stem” that connects the brain to the spinal cord.
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Two development paths
The human brain is divided into three main regions – called forebrain, midbrain and hindbrain – which perform different but interconnected functions.
THE forebrainwhich includes the cerebral hemispheres, is involved in higher-level cognitive processes, such as language, planning, and abstract thinking. The midbrain, the upper part of the brainstem, connects the forebrain and hindbrain and acts as a key relay center for sensory information and movement control. THE hindbrain – which includes the lower part of the brainstem, as well as other structures – also helps coordinate movements and regulate essential functions such as breathing, sleep and heart rate.
Historically, the hindbrain has been difficult to study. One reason is that scientists have faced persistent challenges in generating functional hindbrain neurons under laboratory conditions.
To help understand why, Loh and his team examined the early stages of embryonic development in laboratory mice. They focused on gastrulationthe moment when cells begin to organize themselves into structures that will later form different organs. Researchers identified two distinct populations of immature cells that would give rise to nervous system tissues, including the brain.
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A cell population expressed a gene called otx2which helps direct early development of the forebrain and midbrain. The second group of cells expressed the gene Gbx2which is involved in the development of the midbrain and hindbrain.
This photograph shows a 9.5 day old mouse embryo and represents the two distinct origins of brain development. The forebrain and part of the midbrain (blue) express the Otx2 gene, while the hindbrain and the rest of the midbrain (red) express Gbx2. The red blood cell population also expands into the spinal cord.
(Image credit: Stanford Medicine)
The functions of these genes were already known, but their distinct expression in these two groups of cells was revealed by the new research. The cell populations remained distinct as they developed into neural tissue in their own right, rather than overlapping.
The team also examined chromatinthe molecular structure that tightly packages DNA inside the nucleus and helps regulate which genes a cell can use. The team found that the two cell populations have different chromatin configurations, supporting the idea that they follow distinct developmental pathways.
This could help explain why scientists’ attempts to develop hindbrain neurons have been largely unsuccessful.
“Previous attempts to create hindbrain neurons have likely attempted to coax forebrain and midbrain progenitors into hindbrain cells, which our study suggests is not possible,” study co-author. Rayyan Jokhaigraduate student in Loh’s laboratory, said in a statement.
Why it matters
Thanks to the information discovered during their experiments, the researchers succeeded in guiding humans stem cells to transform into functional motor neurons of the hindbrain, which participate in the control of movement. Specifically, these cells produced proteins characteristic of hard-to-develop regions of the hindbrain that help control facial muscles and those involved in swallowing.
In several neurological diseases, including spinal muscular atrophy And amyotrophic lateral sclerosisMotor neurons deteriorate and affected patients may lose their ability to swallow, speak and breathe independently.
“We can’t take live motor neurons from a patient’s hindbrain to look at how these diseases attack those neurons,” Loh said. “Cultivating these hindbrain motor neurons on a plate allows us to study these diseases.” Looking ahead, the team aims to use their results to study these diseases and identify new treatments.
The new findings could also reveal something fundamental about the evolution of vertebrate animals.
The study authors investigated whether the two developmental pathways were unique to humans or reflected a much older evolutionary arrangement. They looked to previously published data on other species, including macaques (Macaca), zebrafish (Danio Rerio) and chickens (Domestic gallus gallus) – and again found two distinct cell populations expressing the two key genes.
And even in acorn worms – a marine invertebrate whose evolution diverged from vertebrates around 550 million years ago – they again found these two distinct groups of cells.
“The Stanford discovery establishes that the deep ancestry of the vertebrate brain is fundamentally modular,” said Anna Di Cosmoprofessor of biology at the Federico II University of Naples in Italy, who was not involved in the study. “The developmental separation between the anterior lineage (forebrain/midbrain) and the posterior lineage (hindbrain) is visibly ancient,” Cosmo told Live Science in an email.
Loh’s team speculates that these developmental trajectories observed in the womb could suggest that the two cell populations once belonged to two distinct nervous systems. “Later in evolution, these two nervous systems may have been brought together to give rise to the appearance of a single integrated brain,” Loh said.
However, the study does not reveal exactly when the two pathways emerged or how they became integrated. “It’s important to emphasize that this is just an idea and could change as scientists learn more,” Loh said.
Jokhai, RT, Dundes, CE, Ahsan, HS, Kang, RS, Salomon-Shulman, REA, Rajan, A., Kim, YS, Stanton, LJ, Xu, C., Do, S., McDonald, BD, López, JMA, Urrutia, HA, Greenfeld, H., Wong, A., Qu, Y., Petkovic, AS, Miao, Y., Garcia, KC, . . . Loh, K.M. (2026). Two parallel neural ectoderm progenitors contribute to brain development. Natural neuroscience. https://doi.org/10.1038/s41593-026-02433-7
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