Scientists have uncovered two surprising forces that help guide how human brain forms before birth, reshaping understanding of cortex development. Before birth, human brain is shaped in large part by unusual class of stem cells known as radial glia. These cells help determine which brain cells are produced, when they appear, and how cerebral cortex, region involved in thought, memory, and language, develops.
Radial glia give rise to many neurons and supporting cells found in cortex. Scientists believe they also played major role in dramatic expansion of human cortex compared with that of other species. Most radial glia disappear before birth, although cells with similar characteristics can later appear in brain cancers for reasons that are still not fully understood.
“Radial glia are the coolest cells that have ever existed,” said Aparna Bhaduri, assistant professor of biological chemistry at David Geffen School of Medicine at UCLA. “They’re really key to making us human.”
“But they’re also at center of many neurodevelopmental and neuropsychiatric disorders, as well as cancer — so understanding how they make decisions is one way to start understanding how those conditions arise,” Bhaduri added. Two new studies, published in Cell and Science, now provide fresh insight into how these cells decide what to become. Bhaduri and colleagues found radial glia respond to two very different kinds of information: way they process nutrients and direct physical signals coming from another part of developing brain. Together, findings offer clearer picture of how human cortex produces such enormous variety of cells.
Metabolism Helps Direct Brain Stem Cells – Not Just Background Energy
In Cell study, researchers created detailed map of metabolic activity in developing human cortex. Project brought together Bhaduri’s lab and Heather Christofk’s lab and was led by co-first authors Jessenya Mil and Jose Soto. Using donated human tissue along with brain organoids grown from stem cells, researchers found metabolism does more than simply supply energy and raw materials. It can actively influence what developing brain stem cells become.
Radial glia were found to depend heavily on pentose phosphate pathway, metabolic process that uses glucose to make molecular building blocks needed by rapidly dividing cells. When researchers lowered glucose levels or interfered with that pathway, radial glia changed behavior. Instead of producing same mix of cells, they shifted toward making more inhibitory neurons and other cell types that normally emerge later in development.
“What was surprising is that metabolism isn’t just passive thing that happens in background,” said Bhaduri, member of both UCLA Broad Stem Cell Research Center and UCLA Health Jonsson Comprehensive Cancer Center. “It can really control how stem cells make decisions.” Results may help scientists investigate how maternal nutrition, metabolic disorders and other environmental influences affect developing brain. Metabolic atlas created by team also provides one of most detailed resources yet for studying metabolism during human brain development.
A Surprising Signal From Thalamus – Physical Contact Controls Cortex
Second study, published in Science and led by first author Claudia Nguyen, examined very different source of information reaching radial glia. Researchers focused on thalamus, structure deep inside brain that helps relay information throughout nervous system. Scientists have long known neurons in thalamus send out long fibers toward cortex. These thalamic projections eventually connect with specific cortical neurons.
But in humans, anatomical studies have shown fibers arrive well before those final connections are established. That raised important question: Why do projections reach cortex so early? Using human stem cell-derived brain assembloids, UCLA researchers found fibers have another role. During development, projections from thalamus directly touch radial glia.
That physical contact changed what stem cells produced. Radial glia exposed to thalamic projections generated more excitatory neurons, which are cortex’s primary signal-carrying cells. Effect was especially strong for upper-layer neurons, population that has expanded substantially during human brain evolution.
“We already knew that these projections influence how cortex develops,” Bhaduri said. “What we specifically found is that this influence comes through actual physical connection between projections and radial glia — point of contact that just hasn’t been identified before, and one that very likely does not exist in rodents.”
Analysis: Gene Linked To Physical Connection – NRXN1 And Autism
Researchers connected newly identified contact point to NRXN1, gene already known for helping neurons form connections with one another. Mutations in NRXN1 have previously been associated with autism spectrum disorder. To explore its role, team created assembloids using patient-derived cells carrying NRXN1 mutation. Altered thalamic signals behaved differently from those produced by unaffected cells. This changed balance between radial glia and neurons they generated.
Result gives researchers new way to study how very early changes in brain development might influence formation of cortex and potentially contribute to neurological conditions including autism.
Developing Brain Is In Constant Communication – Organoids Changing Study
Although two studies examined very different mechanisms, they point toward same broader idea. One focused on metabolism, while other examined direct physical contact between developing brain regions. In both cases, radial glia were shown to respond continuously to information from surroundings, not acting in isolation.
Findings also demonstrate how brain organoid technology is changing study of human development. Decade ago, scientists had few practical ways to directly investigate how uniquely human neural stem cells behave.
Organoids now make possible to recreate certain features of human brain development in laboratory and test questions that cannot easily be addressed using animal models alone.
Bhaduri hopes findings will help establish broader principle in developmental neuroscience: metabolism and physical connections are not simply supporting processes. They can actively determine how stem cells behave and what kinds of cells they produce.
“Ultimately, these studies give us glimpse under hood of how these cells make decisions,” she said. “Understanding those decisions is first step toward understanding normal brain development, disease vulnerability and, potentially, how similar stem-cell programs operate in brain cancer.”
Q&A
Q: How does human brain form before birth?
A: Before birth, radial glia stem cells guide cortex formation; UCLA studies in Cell and Science show they respond to metabolism pentose phosphate pathway and physical thalamus signals.
Q: How does metabolism affect brain stem cells?
A: Radial glia depend on pentose phosphate pathway using glucose; lowering glucose shifted them to make more inhibitory neurons later than normal.
Q: What surprising signal from thalamus guides brain development?
A: Thalamic fibers directly touch radial glia in human assembloids, boosting excitatory upper-layer neurons; contact likely absent in rodents and linked to NRXN1 autism gene.
FAQ
1. What are radial glia?
Radial glia are unusual stem cells that give rise to neurons and supporting cells in cortex, key to human cortex expansion, disappearing before birth but similar cells appear in brain cancers.
2. Where were two brain formation studies published?
One in Cell led by Jessenya Mil and Jose Soto mapping metabolism, other in Science led by Claudia Nguyen on thalamus signals, both from Aparna Bhaduri lab at UCLA.
3. How did researchers study human brain development?
Using donated human tissue and brain organoids and assembloids grown from stem cells, allowing lab recreation of human-specific development not possible in rodents.
4. What is NRXN1 gene link to autism and brain development?
NRXN1 helps neurons connect; mutations associated with autism spectrum disorder; UCLA patient-derived assembloids showed altered thalamic projections changed radial glia balance.
5. Why are findings important for neurodevelopmental disorders and cancer?
Radial glia at center of neurodevelopmental, neuropsychiatric disorders and cancer; understanding their decisions via metabolism and physical contacts may reveal disease vulnerability origins.
Disclaimer: This article is for informational purposes only and does not constitute medical advice.
