The brain may develop from two distinct types of progenitor cells

For decades, many scientists have thought that a single type of starter cell gives rise to the entire brain. New experiments challenge that fundamental picture, providing evidence that two types of progenitor cells are needed to build complex organs.¹

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The study suggests that one type of progenitor cell forms the hindbrain, a part of the brain involved in basic functions such as heartbeat and breathing. A second type generates two other structures: the forebrain, which supports higher-order functions such as reasoning and planning, and the midbrain. The work was published today in Nature Neuroscience.

“The brain is an organ,” says study co-author Kyle Roe, a developmental biologist at Stanford University in California. “But it’s built in two different parts that connect and work together.”

Not everyone agrees with the study’s conclusion that the brain descends from two cell populations that do not mix. However, one aspect of the research has drawn widespread praise: the authors discovered an efficient way to induce stem cells to grow into hindbrain motor neuron cells, which help control movements such as swallowing. The method could help researchers study diseases that affect these cells, including debilitating neurodegenerative diseases such as motor neuron disease, also known as amyotrophic lateral sclerosis (ALS).

An inescapable developmental fate

Previous research in mouse embryos identified a trademark gene that is widely expressed in brain progenitor cells.² Other studies identified genes expressed in progenitor cells destined to form the front part of the brain,³ as well as another gene expressed in cells destined to form the back.⁴ However, it remained unclear whether these distinct populations were strictly concentrated in specific brain regions.

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To better understand the embryonic origins of hindbrain cells, Lo and his team used tissue staining and RNA sequencing to examine mouse embryos 7.5 days after conception. They identified two mutually exclusive clusters of brain progenitor cells. The scientists then used a red fluorescent marker to tag progenitor cells expressing posterior brain genes and tracked where those cells ended up in the adult brain. “The back half of the brain was red, but the front wasn’t,” Lo said.

The researchers conducted another experiment using human pluripotent stem cells, which can develop into almost any type of adult tissue. They coaxed the cells to transform into two early brain cell types and then exposed them to chemical signals associated with different brain regions.

Some cells matured quickly when given signals that produce the forebrain and midbrain. But when researchers provided the signal associated with the hindbrain, those cells failed to progress, Lo says. The results suggested that their cell fate was already fixed.

Evidence across species

Finally, the researchers looked for evidence of dual ancestry across a wide range of species, including monkeys, chickens and zebrafish. They found two types of brain precursors throughout these species.

The same pattern was also found in Saccoglossus kowalevskii, a marine invertebrate known as an acorn worm. That surprised the researchers. The last shared ancestor of humans and acorn worms “lived more than 500 million years ago, before the supercontinent Pangea, but its developing embryo looked exactly like a mouse embryo,” one researcher notes.