Summary

Experiments in mouse embryos, human pluripotent stem cells and other species suggest that the brain develops from two distinct progenitor populations. The study also reports an efficient route to hindbrain motor-neuron cells for laboratory disease research.

Experiments in mouse embryos and human pluripotent stem cells challenge the long-held idea that one type of early progenitor cell gives rise to the entire brain. The study, published in Nature Neuroscience, provides evidence for two distinct populations of brain progenitor cells with different developmental destinations.

Progenitor cells are early cells that can produce more specialised descendants. In this study, one population generated the hindbrain, which supports basic functions including heartbeat and breathing. The other produced the forebrain and midbrain, regions involved in higher-order functions such as reasoning, planning and movement-related processing.

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Two developmental lineages

The researchers first examined mouse embryos 7.5 days after conception using tissue staining and RNA sequencing. They identified two mutually exclusive clusters of brain progenitor cells. This means that the cells marked as belonging to one cluster were separate from those carrying the other set of developmental markers.

The team then used red fluorescent markers to label precursor cells expressing a gene associated with the back of the brain. Tracking those cells into the mature brain showed red-labelled cells in the hindbrain but not in the forebrain. The result supported the idea that the marked progenitors were committed to a specific region rather than contributing broadly across the brain.

The findings revise the developmental picture from a single starting population to two early populations that later form connected parts of one organ. The researchers describe the brain as a structure built from two developmental components that work together.

Stem-cell tests of developmental fate

A separate set of experiments used human pluripotent stem cells. These cells can develop into nearly every type of adult tissue, making them useful for studying how developmental decisions are made in the laboratory.

The researchers guided the cells towards the two early brain cell types and then exposed them to chemical signals that normally promote different brain regions. One cell type matured readily when given signals for forebrain and midbrain development. When exposed to signals intended to produce hindbrain cells, however, it did not progress.

This response suggests that the two populations had already acquired different developmental fates before those later chemical signals were applied. The result strengthens the case that the distinction is not simply a temporary change in gene activity during brain formation.

An ancient pattern and a laboratory application

The researchers also looked for the two progenitor populations in several species, including monkeys, chickens, zebrafish and the acorn worm Saccoglossus kowalevskii. They found the two varieties in every species examined. Because the evolutionary ancestor shared by humans and acorn worms lived more than 500 million years ago, the pattern may be deeply conserved across animal evolution.

The study also produced a practical stem-cell result. The researchers found an efficient way to generate hindbrain motor-neuron cells. These neurons help control movements such as swallowing, and their loss is involved in debilitating conditions including motor neuron disease, also known as amyotrophic lateral sclerosis (ALS).

The method could provide cells for laboratory studies of how such diseases develop and how potential treatments affect them. Its immediate significance is as a research tool for producing a difficult-to-generate cell type, rather than as a clinical treatment.

The interpretation that the brain originates from two progenitor populations that do not mix is not universally accepted. Even so, the experiments provide a coherent set of developmental, stem-cell and comparative evidence for a more divided origin of the brain than the traditional single-progenitor model proposed.

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