TOKYO —

The intricate architecture of the human brain, a marvel of biological engineering, is meticulously constructed before birth through an astonishing cascade of cellular decisions. At the very heart of this developmental process are radial glial cells, a specialized class of stem cells that play a pivotal role in shaping many of the distinctive characteristics that set the human brain apart. These remarkable cells are the primary architects, generating the vast quantities of neurons and crucial support cells that constitute the cerebral cortex, the brain’s command center for cognition, memory, and language. Moreover, radial glia are strongly implicated in the disproportionately large expansion of the human cortex when compared to that of other species. While the majority of these progenitor cells typically vanish before birth, a perplexing phenomenon occurs where similar cells can re-emerge in brain cancers, a reawakening whose underlying reasons remain a significant enigma for scientists.

"Radial glia are the coolest cells that have ever existed," stated Aparna Bhaduri, an assistant professor of biological chemistry at the David Geffen School of Medicine at UCLA, underscoring their profound significance. "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."

Two groundbreaking studies, recently published in the prestigious journals Cell and Science, now offer an unprecedentedly detailed look into the mechanisms by which radial glia navigate these critical developmental choices. In a collaborative effort, Bhaduri and her colleagues have illuminated how these cells respond to a dual input of information: the intricate metabolic processes they undergo and direct physical signals emanating from other developing brain regions. Collectively, these findings provide profound new insights into the complex processes that enable the human cortex to generate its astonishing diversity of cell types.

Metabolism: A Guiding Hand for Brain Stem Cells

The Cell study, a landmark achievement in neurodevelopmental research, meticulously mapped the metabolic landscape of the developing human cortex. This ambitious project was a testament to the power of interdisciplinary collaboration, bringing together the expertise of Bhaduri’s laboratory and that of Heather Christofk. The research was spearheaded by co-first authors Jessenya Mil and Jose Soto, whose dedication was instrumental in its success.

To construct this comprehensive atlas, the research team analyzed both donated human brain tissue and meticulously engineered brain organoids, three-dimensional structures grown from stem cells that mimic early brain development. The results of their analysis led to a surprising revelation: metabolism is not merely a passive support system for brain development, operating in the background. Instead, it actively dictates and influences the types of cells that are ultimately produced.

A key finding was the profound reliance of radial glia on the pentose phosphate pathway. This metabolic process is crucial for rapidly dividing cells, as it efficiently utilizes glucose to generate the essential molecular building blocks required for proliferation. When the researchers experimentally reduced the availability of glucose or disrupted this critical pathway, a discernible shift occurred in the stem cells’ output. They began to generate a higher proportion of inhibitory neurons and other cell types that typically emerge later in the developmental timeline.

"What was surprising is that metabolism isn’t just a passive thing that happens in the background," Bhaduri emphasized, also noting her affiliations with the UCLA Broad Stem Cell Research Center and the UCLA Health Jonsson Comprehensive Cancer Center. "It can really control how stem cells make decisions."

These findings hold significant implications for future research, potentially enabling scientists to investigate how factors such as maternal nutrition, metabolic disorders, and broader environmental influences can impact the developing human brain. The metabolic atlas itself represents one of the most detailed and invaluable resources to date for researchers dedicated to unraveling the complexities of metabolism during human brain development.

An Early Signal from the Thalamus Shapes Cortical Development

Complementing the metabolic insights, the second study, published in Science and led by first author Claudia Nguyen, explored an entirely different avenue of developmental influence: signals originating from the thalamus. This structure, nestled deep within the brain, serves as a critical relay station for sensory and motor signals throughout the nervous system.

For years, neuroscientists have known that neurons within the thalamus extend long, slender projections towards the developing cortex. These projections, akin to nascent wiring, eventually establish connections with specific cortical neurons. However, anatomical studies had previously revealed a curious detail: in humans, these thalamic projections reach the cortex at a remarkably early stage, long before the intricate synaptic connections are fully formed. This observation prompted a crucial question: what is the purpose of this premature arrival?

Employing sophisticated human stem cell-derived brain "assembloids"—more complex organoid models that integrate multiple brain regions—the UCLA researchers uncovered a significant part of the answer. They discovered that these developing thalamic projections physically interact with radial glia during the critical period of brain formation.

This direct physical contact was found to profoundly alter the behavior of the radial glia. Specifically, it stimulated them to produce a greater number of excitatory neurons, the primary type of neuron responsible for transmitting signals throughout the cortex. This effect was particularly pronounced for upper-layer neurons, a class of cells that are notably expanded in the human brain, contributing significantly to its advanced cognitive capabilities.

"We already knew that these projections influence how the cortex develops," Bhaduri explained. "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." This anatomical difference likely underscores the unique evolutionary trajectory of the human brain.

The Role of a Gene Linked to Autism Spectrum Disorder

The researchers further established a critical link between this physical interaction and the NRXN1 gene. This gene is already well-established for its role in facilitating the formation of neuronal connections. Crucially, mutations in NRXN1 have been previously associated with autism spectrum disorder (ASD), a neurodevelopmental condition characterized by significant challenges in social interaction and communication.

To investigate the precise role of NRXN1 in this context, the team engineered assembloids using patient-derived cells that carried a known NRXN1 mutation. In these experimental models, the altered thalamic signals, influenced by the mutated gene, behaved distinctly from those generated by cells with unaffected NRXN1.

These molecular and cellular changes rippled through the developmental process, shifting the delicate balance between the self-renewal of stem cells and the generation of neurons. The findings offer a compelling new avenue for researchers to explore how subtle disturbances in early brain development, potentially mediated by genes like NRXN1, can contribute to the formation of the cortex and influence neurodevelopmental outcomes.

A Symphony of Communication in the Developing Brain

While these two studies investigated disparate mechanisms—one focusing on the internal metabolic environment and the other on external neural connections—they converge on a unifying principle: radial glia do not operate in developmental isolation. Their behavior and the fate of the cells they produce are continuously and dynamically shaped by a complex interplay of signals from their surrounding environment.

These pioneering investigations also highlight the transformative impact of organoid technology on the study of human brain development. A mere decade ago, scientists possessed limited practical tools to directly probe the behavior of uniquely human neural stem cells. Today, advanced models like brain organoids and assembloids provide unprecedented opportunities to recapitulate key aspects of human brain development in a controlled laboratory setting. These systems are invaluable for testing hypotheses that cannot be adequately addressed using traditional animal models, which often exhibit significant differences in brain structure and development.

Bhaduri expressed her hope that these findings will encourage the scientific community to reframe their understanding of metabolism and physical cellular interactions. She advocates for viewing them not as passive background processes, but as active, dynamic drivers of development.

"Ultimately, these studies give us a glimpse under the hood of how these cells make decisions," she concluded. "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."

The research was generously supported by a consortium of esteemed funding bodies, including 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. This broad base of support underscores the national and international recognition of the significance and potential impact of this groundbreaking work.