For decades, developmental biologists assumed the brain arose from a single progenitor cell during early development. New research from Stanford Medicine challenges this foundational model, revealing instead that the human brain consists of two ancient nervous systems that evolved independently and developed along parallel—not converging—pathways.
Led by Kyle Loh, the study examined embryonic development at the gastrulation stage, when the body first takes shape. Graduate students Rayyan Jokhai and Carolyn Dundes identified two distinct brain progenitor cells with different genetic markers. One cell population expresses a gene called Otx2 and becomes the forebrain and midbrain, which handle higher-level thinking like language, consciousness, and abstract reasoning. The other expresses Gbx2 and forms the hindbrain, also called the brain stem, which controls essential automatic functions: breathing, heartbeat regulation, and hunger signals.
Crucially, the researchers found these two cell populations never overlap and remain “mutually exclusive from the earliest stages of development.” By examining the DNA packaging, or chromatin, in these cells, they discovered the anterior neural ectoderm (future forebrain and midbrain) and posterior neural ectoderm (future hindbrain) have fundamentally different chromatin configurations. These structural differences essentially lock each progenitor cell into its respective developmental fate, like “travelers on parallel tracks that never cross.”
This finding explains a decades-long puzzle in neuroscience: why researchers struggled to grow certain hindbrain neurons in the laboratory. “Previous attempts to make hindbrain neurons likely tried to coax forebrain and midbrain progenitors into hindbrain cells, which our study shows is not possible,” Jokhai said. Scientists had been trying to convert one progenitor type into another it was fundamentally incapable of becoming.
Armed with this knowledge, the team successfully coaxed human pluripotent stem cells to become functional hindbrain motor neurons in culture for the first time. The lab-grown neurons displayed authentic hindbrain characteristics, including electrical activity and proteins identifying brain segments controlling facial and swallowing muscles.
The evolutionary implications are profound. The same two-origin pattern appears in chickens, zebrafish, and acorn worms—creatures sharing a distant common ancestor with humans. This suggests evolution packaged two existing neural systems together spatially, creating what we perceive as a single organ.
The findings, published in Nature Neuroscience on September 18, have immediate clinical relevance. The ability to grow hindbrain neurons opens new research avenues for devastating diseases affecting the brain stem, including spinal muscular atrophy (SMA), a leading genetic cause of death in infants, and amyotrophic lateral sclerosis (ALS). Both conditions involve progressive loss of hindbrain neuron function, leading to difficulties swallowing and breathing. Until now, studying these diseases has been nearly impossible because scientists cannot obtain living brain stem tissue from patients.
Key facts
- The brain develops from two separate progenitor cells rather than one, overturning a prevailing model of brain development.
- The forebrain and midbrain originate from cells expressing Otx2, while the hindbrain originates from cells expressing Gbx2; these populations never overlap.
- The anterior and posterior neural ectoderm have fundamentally different chromatin configurations that lock each into its developmental fate.
- Researchers successfully grew functional hindbrain motor neurons in culture for the first time using human pluripotent stem cells.
- The two-origin brain pattern exists in chickens, zebrafish, and acorn worms, suggesting this developmental mechanism is ancient and evolutionarily conserved.
- This discovery may help researchers develop treatments for spinal muscular atrophy and amyotrophic lateral sclerosis, which damage hindbrain neurons.