Stanford Study Reveals Two Neural Systems in Brain Development

The brain is an organ of staggering complexity, and scientists are still only beginning to understand how it is formed in the first place.

In a paper published today in Nature Neuroscience, a Stanford-led team reports that human and animal brains consist of two co-operating neural systems, which begin developing alongside one another at the earliest stages of an embryo.

The findings indicate that distinct brain regions emerge from different types of embryonic cells, called progenitors. One progenitor cell type gives rise to the forebrain and midbrain, whereas another follows an entirely separate developmental route to create the hindbrain.

Two progenitor cell types shape brain development

The researchers first identified this division by examining mouse brain development during gastrulation, an extremely early embryonic phase.

They then showed that human pluripotent stem cells can take the same developmental routes according to the signals they receive. In a scientific first, the team induced human stem cells to form hindbrain motor neurons with electrical activity and proteins characteristic of those cells.

Progenitor cells that generate the forebrain and midbrain produce a particular protein through a gene known as Otx2. Cells destined for the hindbrain, by contrast, express a gene called Gbx2.

Although both progenitor types provide the foundations of the full organ we call the brain, they cannot substitute for one another. Their DNA packaging also differs at a fundamental level, producing entirely separate chromatin ‘landscapes’.

This distinction could help explain why laboratory efforts to grow cells that make up the hindbrain have frequently been unsuccessful. Researchers may have started with the wrong cellular building blocks: cells programmed to become forebrain tissue.

"In stem cell biology, people are always fixated with creating the end cell type, like the neuron… But it's important to begin at the earliest stages of embryonic development," says developmental biologist Rayyan Jokhai, who is co-first author with his colleague Carolyn Dundes on the paper.

"Our careful attention to that early time point allowed us to find this fundamental split in brain development," Jokhai adds.

Implications for brainstem disease research

This aspect of the work could speed up research into diseases affecting the brainstem, which controls some of the body's most fundamental functions.

Beyond its potential medical value, the discovery also prompts numerous questions about the evolutionary past of animal brains.

"Our research suggests that evolution took two existing neural systems and pushed them together spatially," says developmental biologist Kyle Loh, whose lab hosted the research.

"Having the brain as one organ would probably be more efficient, but we rely on this primordial way to make the brain as two separate pieces."

"I was surprised at our findings because the word 'brain' implies a contiguous organ that likely has a singular origin," Jokhai says.

"But even 500 million years ago, there were these separate neural systems, which now almost operate as one, which is very cool."

An evolutionary two-part brain blueprint

These comments require some further context. Loh and Jokhai are not claiming that the neural systems necessarily began as two distinct organs.

Instead, they are making an evolutionary inference from the way modern animal brains develop during gastrulation.

The team observed this composite brain system - in which two progenitor cell types work together to produce a complete organ - at the gastrulation stage in embryos of modern mice, macaques, chickens, zebrafish and acorn worms.

Each of these animals shares a common ancestor on the evolutionary tree of life. Scientists estimate that they diverged from that single branch roughly 550 million years ago.

The research therefore suggests that animal brains, including the human brain, have followed this two-part plan for hundreds of millions of years.

However, the current evidence cannot establish whether the two components evolved separately. That will need to be investigated in future research.

The research was published in Nature Neuroscience.

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