Two pathways from the beginning
A Stanford Medicine-led team has found that the human brain develops from two distinct groups of progenitor cells rather than from one shared population, a result that changes a long-standing model of early brain formation. The findings were published on September 18 in Nature Neuroscience.
The researchers traced the split to gastrulation, the early embryonic stage when the body begins to take shape. In mouse embryos, one progenitor population expressed the gene Otx2 and went on to form the forebrain and midbrain. A second population expressed Gbx2 and produced the hindbrain. The two populations did not overlap, indicating that the pathways run in parallel from the earliest stages examined.
The team also studied chromatin, the packaging that helps determine which genes a cell can access. Cells destined for the front and rear portions of the brain had fundamentally different chromatin configurations. Those differences help explain why previous attempts to turn forebrain or midbrain progenitors into hindbrain neurons have proved difficult: the starting cells were already committed to another developmental route.
A practical result for cell research
Using the developmental distinction, the scientists coaxed human pluripotent stem cells into functional hindbrain motor neurons in the laboratory. The resulting cells generated electrical action potentials and produced proteins associated with regions that control facial and swallowing muscles.
That ability could expand research into disorders involving the brain stem. Hindbrain neurons regulate automatic functions including breathing, sleep, heartbeat and hunger, while also controlling muscles used in speech and swallowing. Scientists cannot take living brain-stem tissue from patients, making laboratory models particularly important for conditions such as spinal muscular atrophy and amyotrophic lateral sclerosis. Both diseases can impair neurons involved in swallowing and breathing.
The result does not mean that an adult person has two independently operating brains. Rather, it describes two ancient developmental origins that are joined into the contiguous structure commonly called the brain. The forebrain supports functions including language, consciousness and abstract reasoning, while the hindbrain manages many essential automatic processes.
An evolutionary pattern
The researchers compared the developmental pattern across species and reported the same two-origin arrangement in chickens, zebrafish and acorn worms. Jellyfish, which diverged from the human lineage hundreds of millions of years ago, also possess separate nervous systems at opposite ends of the body. The team interprets that evidence as suggesting evolution brought two older neural systems together spatially.
Senior author Kyle Loh, an associate professor of developmental biology, led the work, with graduate students Carolyn Dundes and Rayyan Jokhai as co-first authors. The immediate contribution is both conceptual and experimental: a revised account of how the brain begins, paired with a method for making a class of neurons that has been unusually hard to study.
