Before birth, the human brain is assembled through an enormous series of cellular choices. At the center of this process is radial glia, a special type of stem cell that helps create many of the characteristics that distinguish the human brain.
These cells produce a large number of neurons and supporting cells that form the cerebral cortex, the region of the brain involved in thinking, memory and language. Radial glia are also thought to contribute to the unusually large expansion of the human cortex compared to that of other species. Although most disappear before birth, similar cells can reappear later in brain cancers for reasons scientists still don’t fully understand.
“Radial glia are the coldest cells that have ever existed,” said Aparna Bhaduri, assistant professor of biological chemistry at the David Geffen School of Medicine at UCLA. “They are really key to making us human. But they are also at the center of many neurodevelopmental and neuropsychiatric disorders, as well as cancer, so understanding how they make their decisions is one way to begin to understand how those conditions arise.”
Two new studies published in Cell and Science We now offer a closer look at how radial glia make those developmental decisions. Bhaduri and her colleagues discovered that cells respond to two very different types of information: the way they process nutrients and direct physical signals from another part of the developing brain. Together, these findings offer new insights into how the human cortex produces its remarkable variety of cell types.
Metabolism helps direct brain stem cells
In it Cell In the study, the researchers built a detailed map of metabolism in the developing human cortex. The project was a collaboration between Bhaduri’s lab and Heather Christofk’s lab and was led by co-authors Jessenya Mil and José Soto.
To create the atlas, the team analyzed donated human tissue along with brain organoids grown from stem cells. Their results led to an unexpected conclusion: metabolism does not simply support brain development in the background. It can actively influence what types of cells are produced.
The researchers found that radial glia rely heavily on the pentose phosphate pathway, a metabolic process that uses glucose to produce materials needed by rapidly dividing cells.
When scientists reduced the amount of glucose available or interfered with this pathway, the stem cells changed what they produced. They began to generate more inhibitory neurons and other types of cells that normally appear later in development.
“The surprising thing is that metabolism is not just something passive that happens in the background,” said Bhaduri, a member of the UCLA Broad Stem Cell Research Center and the Jonsson Comprehensive Cancer Center at UCLA Health. “You can really control how stem cells make decisions.”
The results could help scientists investigate how maternal nutrition, metabolic disorders and other environmental influences affect the developing brain. The metabolic atlas also provides one of the most detailed resources yet for researchers studying metabolism during human brain development.
A signal arrives early from the thalamus.
The second study, published in Science and led by first author Claudia Nguyen, examined an entirely different source of developmental information. This time, the researchers focused on signals coming from the thalamus, a deep structure in the brain that helps transmit information to the entire nervous system.
Scientists have known for years that neurons in the thalamus send long projections to the cortex. These cable-like fibers eventually form connections with specific cortical neurons. However, anatomical studies have shown that in humans projections reach the cortex long before those final connections are made.
This raised an important question: why do fibers arrive so early?
Using brain “assemblies” derived from human stem cells, UCLA researchers found part of the answer. Thalamic projections physically touch the radial glia while the brain is still developing.
That contact changed the behavior of the stem cells. It made them produce more excitatory neurons, the main signal-carrying neurons in the cortex. The effect was especially strong in the neurons of the upper layer, which are particularly expanded in the human brain.
“We already knew that these projections influence how the crust develops,” Bhaduri said. “What we found specifically is that this influence occurs through an actual physical connection between the projections and radial glia, a point of contact that simply has not been identified before and that most likely does not exist in rodents.”
A gene linked to autism enters the scene
The researchers connected this physical interaction to NRXN1, a gene already known to help neurons form connections with each other. Mutations in NRXN1 have previously been associated with autism spectrum disorder.
To investigate its role, the team created assemblies from cells derived from patients carrying an NRXN1 mutation. In these models, altered thalamic signals behaved differently than signals emitted by unaffected cells.
These changes changed the balance between the number of stem cells and the neurons they generated. The result offers researchers a possible way to study how early alterations in brain development could influence the formation of the cortex.
The developing brain is in constant communication.
Although the two studies focused on very different mechanisms, they point toward the same broader idea. One examined metabolism, while the other explored neuronal connections, but both showed that radial glia do not make their decisions in isolation. Their behavior is continually shaped by cues from the environment around them.
The studies also demonstrate how dramatically organoid technology has changed the study of human brain development. About a decade ago, scientists had few practical ways to directly investigate how uniquely human neural stem cells behave.
Today, brain organoids and related models allow researchers to recreate important features of human brain development in the laboratory. These systems also make it possible to test questions that cannot be addressed using animal models alone.
Bhaduri hopes the findings will encourage scientists to view metabolism and physical cellular connections as active drivers of development rather than secondary processes.
“Ultimately, these studies give us insight into how these cells make decisions,” he said. “Understanding those decisions is a first step toward understanding normal brain development, vulnerability to disease, and potentially how similar stem cell programs work in brain cancer.”
This research was supported by the National Institutes of Health, the National Science Foundation, the Brain & Behavior Research Foundation, the Alfred P. Sloan Foundation, the Rose Hills Foundation, the Esther A. & Joseph Klingenstein Fund, the Simons Foundation, the Chan Zuckerberg Initiative, the NIH BRAIN Cell Atlas Network Initiative, the International Foundation for Ethical Research, the UCLA Stem Cell Research Center Stem Cell Research Training Program, and the Jonsson Comprehensive Cancer Center. from UCLA Health and the Ablon Fellowship Program of the UCLA Broad Stem Cell Research Center.