For over a century, neuroscientists have understood the brain as a single unified organ. A Stanford Medicine-led study published in Nature Neuroscience on September 18 challenges this view, revealing that the human brain actually consists of two ancient nervous systems that evolved independently and were later packaged together.
The research, led by Kyle Loh, PhD, associate professor of developmental biology, shows that the forebrain and midbrain arise from a completely different progenitor cell than the hindbrain. This discovery overturns the prevailing model that a single progenitor cell early in development gives rise to the entire brain, with all parts sharing a common developmental origin.
The adult brain has three main regions. The forebrain handles higher-level thinking—language, consciousness, and abstract reasoning. The hindbrain, located at the back of the skull and often called the brain stem, controls essential automatic functions: breathing, sleeping, regulating heartbeat and hunger, and controlling the muscles of the face, tongue, and throat.
The researchers made their discovery by studying the earliest moments of embryonic development during gastrulation, when the body first takes shape. Using developing mouse embryos, graduate students Carolyn Dundes and Rayyan Jokhai identified two different brain progenitor cells. One expresses a gene called Otx2 and becomes the forebrain and midbrain. The other expresses Gbx2 and forms the hindbrain. These cell populations never overlap and are mutually exclusive from the earliest stages of development.
The team also examined chromatin—the way cells package DNA—in these cells. They found that the anterior and posterior neural ectoderm have fundamentally different chromatin configurations, essentially locking each progenitor cell into its respective fate.
This finding explains decades of scientific frustration. Previous attempts to grow certain brain cells in laboratories failed because researchers were trying to coax forebrain progenitors into becoming hindbrain cells, which is fundamentally impossible. Armed with this knowledge, the Stanford team successfully grew human hindbrain motor neurons in the laboratory for the first time, displaying authentic hindbrain characteristics including electrical activity and proteins identifying segments controlling facial and swallowing muscles.
The researchers traced this two-origin pattern across 550 million years of evolutionary history, finding it in chickens, zebrafish, and acorn worms. According to Loh, “evolution took two existing neural systems and pushed them together spatially.”
The discovery has significant implications for studying diseases affecting the brain stem. Spinal muscular atrophy (SMA) is a leading genetic cause of death in children under age 1. Amyotrophic lateral sclerosis (ALS) typically appears between ages 40 and 70. Both diseases involve hindbrain neurons gradually ceasing to function, causing patients to lose the ability to swallow and eventually breathe. The ability to grow hindbrain neurons in dishes opens new possibilities for understanding disease mechanisms and developing treatments.
Key facts
- Stanford researchers found that the forebrain and hindbrain develop from two separate progenitor cells, not a single common origin
- The forebrain handles higher-level thinking while the hindbrain controls automatic functions like breathing and heartbeat
- Previous laboratory attempts to grow hindbrain neurons failed because researchers were trying to convert forebrain cells, which is developmentally impossible
- The two-origin brain pattern appears across species dating back 550 million years, including chickens, zebrafish, and acorn worms
- The discovery could accelerate research into brain stem diseases like spinal muscular atrophy and ALS