Two New Studies Reveal How Brain Stem Cells Decide What to Build

Before birth, the human brain is assembled through an enormous series of cellular choices. At the center of this process are radial glia, stem cells that produce many of the neurons and support cells making up the cerebral cortex, the brain region involved in thought, memory and language. Two new studies, published in Cell and Science, now give a closer look at how radial glia make those choices.

"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."

In the Cell study, led by co-first authors Jessenya Mil and Jose Soto, Bhaduri's lab worked with Heather Christofk's lab to build a detailed map of metabolism in the developing human cortex, using donated tissue and stem-cell-grown brain organoids. They found radial glia depend heavily on the pentose phosphate pathway, a process that uses glucose to make materials for rapidly dividing cells. When the scientists lowered available glucose or interfered with the pathway, the stem cells produced more inhibitory neurons and other cell types that normally appear later in development.

The Science study, led by first author Claudia Nguyen, examined signals arriving from the thalamus, a structure deep in the brain. Using human stem-cell-derived brain "assembloids," the researchers found that thalamic projections physically touch radial glia early in development, before final connections form, prompting the stem cells to produce more excitatory neurons, especially the upper-layer neurons that are particularly expanded in the human brain.

The team linked this physical contact to NRXN1, a gene already known for helping neurons connect and previously associated with autism spectrum disorder. In assembloids built from patient-derived cells carrying an NRXN1 mutation, the altered thalamic signals changed the balance between stem cells and the neurons they generated.