The front and back of the human brain do not grow from a single common source but instead arise from two entirely separate populations of embryonic cells, according to a Stanford Medicine study published Sept. 18 in Nature Neuroscience. The findings challenge a long-standing assumption that the vertebrate nervous system develops from one continuous progenitor lineage.
Working with mouse embryos, the research team traced the forebrain and midbrain — the regions responsible for reasoning, memory and sensory processing — to progenitor cells marked by the gene Otx2. The hindbrain, which governs heartbeat, breathing and other automatic functions, instead arose from a distinct population marked by the gene Gbx2. The two lineages diverge early in development and never mix, the researchers found.
A Pattern That Predates Vertebrates
The team then looked for the same split in other animals, finding the two-lineage pattern in chickens and zebrafish, and, notably, in acorn worms — burrowing marine creatures that share a distant common ancestor with humans from roughly 550 million years ago, according to Stanford Medicine's account of the research. Jellyfish, whose lineage diverged from ours even earlier, already carry two separate nerve nets at opposite ends of their bodies, which the researchers say hints the split predates the nervous systems of most modern animals rather than emerging within vertebrates alone.
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.
Kyle Loh, PhD, senior author, associate professor of developmental biology, Stanford Medicine
Rayyan Jokhai, a graduate student and co-first author on the paper, said the finding also explains why past attempts to grow certain neurons in the lab kept failing: "Previous attempts to make hindbrain neurons likely tried to coax forebrain and midbrain progenitors into hindbrain cells, which our study shows is not possible." Using the newly identified Gbx2-marked cells, the team reported it could grow hindbrain neurons directly in a dish for the first time — a tool they say could help researchers study brainstem-linked conditions such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy, both of which involve degeneration in hindbrain-adjacent circuitry.
The work was conducted in mouse embryos and cultured cells, not human embryos, so the exact timing and regulation of the split in human development has not been directly confirmed; researchers are inferring the human pattern from evolutionary conservation across species rather than observing it directly in people. Loh's team says its next step is applying the lab-grown hindbrain neurons to disease models, while other researchers are expected to test whether the same two-lineage split holds across additional vertebrate species.
