How the developing human brain takes instructions: Two UCLA studies reveal what guides its most important stem cells

Key takeaways

• In two new studies, UCLA researchers used lab-grown brain organoids, donated human tissue and fused "assembloids" to investigate how radial glia - the stem cells that build the human cerebral cortex - decide which types of brain cells to make.
• One study showed that how neural glia process nutrients helps determine which neurons they make. The other showed that physical contact from a neighboring region - the thalamus - drives the same cells to produce more of the neurons most expanded in the human brain.
• Together, the findings recast radial glia's surroundings - its nutrients and physical connections - as active drivers of human brain development, offering new insight into how the cortex is built and how that process can go awry in neurodevelopmental disorders and cancer.

As the human brain takes shape before birth, a remarkable type of stem cell helps give it many of the features that make it distinctly human. These cells, called radial glia, make billions of decisions that determine which kinds of brain cells are created, when they appear and how the cortex - the seat of thought, memory and language - takes form.

They generate many of the neurons and support cells of the cerebral cortex and are thought to drive much of its expansion in humans compared with other species. And although they largely disappear before birth, cells resembling them can reemerge, for reasons that remain unclear, in brain cancers.

"Radial glia are the coolest cells that have ever existed," said Aparna Bhaduri, an assistant professor of biological chemistry at the David Geffen School of Medicine at UCLA. "They're really key to making us human. But they're 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 start understanding how those conditions arise."

In two new studies, published in Cell and Science, Bhaduri and her colleagues reveal how radial glia make those decisions - showing that the cells draw on two very different kinds of information: how they process nutrients, and physical signals arriving from another region of the developing brain. Together, the findings help explain how the human cortex builds its staggering cellular diversity.

Metabolism helps shape stem cell fate

In the Cell study - a collaboration between Bhaduri's lab and Heather Christofk's lab and led by co-first authors Jessenya Mil and Jose Soto - researchers created a detailed metabolic atlas of the developing human cortex using donated human tissue and stem cell-derived brain organoids. The work revealed an unexpected role for metabolism itself in shaping brain development.

The team found that radial glia rely heavily on a metabolic process known as the pentose phosphate pathway, which uses glucose to generate building blocks needed for rapidly dividing cells.

When researchers reduced glucose availability or disrupted that pathway, the stem cells changed the types of cells they produced, shifting toward generating more inhibitory neurons and other later-arising cell types.

"What was surprising is that metabolism isn't just a passive thing that happens in the background," said Bhaduri, a member of both the UCLA Broad Stem Cell Research Center and the UCLA Health Jonsson Comprehensive Cancer Center. "It can really control how stem cells make decisions."

The findings could help researchers better understand how maternal nutrition, metabolic disorders and other environmental factors influence brain development. The metabolic atlas also gives scientists one of the most comprehensive resources to date for studying metabolism in the developing human brain.

An early message from the thalamus

The second study, published in Science and led by first author Claudia Nguyen, focused on a very different source of instructions: signals arriving from the thalamus, a deep-brain structure that relays information throughout the nervous system.

Researchers have long known that thalamic projections - the long, wire-like fibers that thalamic neurons extend toward the cortex - eventually connect with specific neurons there. But anatomical studies showed that the projections arrive much earlier in humans than when those final connections form, raising a longstanding question: What are they doing there so early?

Using human stem cell-derived brain "assembloids," the UCLA team uncovered one answer. They found that projections extending from the thalamus make direct physical contact with radial glia during development.

That contact prompted the stem cells to produce more excitatory neurons, the cortex's main signal-carrying cells, and especially the upper-layer neurons most expanded in the human brain.

"We already knew that these projections influence how the cortex develops," Bhaduri said. "What we specifically found is that this influence comes through an actual physical connection between the projections and the radial glia - a point of contact that just hasn't been identified before, and one that very likely does not exist in rodents."

The team traced that physical connection to NRXN1, a gene best known for helping neurons build the connections between them. Mutations in NRXN1 have previously been linked to autism spectrum disorder. When the team built assembloids from patient-derived cells carrying an NRXN1 mutation, the mutant thalamic signals did not behave like those from unaffected cells, shifting the balance between stem cells and the neurons they produced. The finding offers a potential avenue for investigating how disruptions in early brain development may affect the formation of the cortex.

A brain built through constant communication

Although the two studies investigated very different biological processes - one centered on metabolism and the other on neural connectivity - both arrived at a similar conclusion: The developing brain is shaped by continuous communication between stem cells and their surroundings.

The findings also highlight how organoid technologies have transformed developmental neuroscience. Just a decade ago, researchers had few ways to directly examine how uniquely human neural stem cells functioned. Today, organoids allow scientists to model human-specific features of brain development and test ideas that cannot be explored in animal models alone.

Looking ahead, Bhaduri hopes the studies will help establish a broader principle for the field: that metabolism and physical connections are not merely background features of development but active regulators of stem-cell behavior.

"Ultimately, these studies give us a glimpse under the hood of how these cells make decisions," she said. "Understanding those decisions is a first step toward understanding normal brain development, disease vulnerability and, potentially, how similar stem-cell programs operate 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 Initiative Cell Atlas Network, the International Foundation for Ethical Research, the UCLA Broad Stem Cell Research Center's Stem Cell Research Training Program, and the UCLA Health Jonsson Comprehensive Cancer Center and UCLA Broad Stem Cell Research Center Ablon Scholars Program.