How the developing human brain takes instructions: Two studies reveal what guides its most important stem cells
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.
Two groundbreaking studies have unveiled the factors that guide the development of the human brain's most crucial stem cells, called radial glia. Radial glia play a pivotal role in generating various brain cells, shaping the cortex—the region responsible for thought, memory, and language. These cells, which dwindle before birth, have been linked to neurodevelopmental disorders and even certain types of cancer.
In the first study, published in Cell, researchers collaborated with Heather Christofk s lab to create a comprehensive metabolic atlas of the developing human cortex. They discovered that radial glia depend primarily on a metabolic process called the pentose phosphate pathway, which converts glucose into essential building blocks for rapidly dividing cells.
When glucose levels were reduced or the pathway was disrupted, radial glia shifted their production to generate more inhibitory neurons and later-arising cell types. This highlights the pivotal role of metabolism in determining the fate of these stem cells.
The second study, published in Science, focused on the role of thalamic signals in shaping the developing cortex. Thalamic projections, long-wire-like fibers that extend from the thalamus to the cortex, have been known to connect with specific neurons. However, their presence during early development was puzzling. Using human stem cell-derived brain "assembloids," the UCLA team found that thalamic projections make direct physical contact with radial glia, prompting these cells to produce more excitatory neurons, particularly the upper-layer neurons that are most expanded in the human brain.
This discovery of a physical connection challenging prior understanding in rodents suggests that early brain development is influenced by direct communication between thalamic signals and radial glia.
These findings reveal that the developing brain is shaped by a continuous exchange of information between stem cells and their environment. The studies emphasize the importance of metabolism and neural connectivity as active regulators of stem-cell behavior, rather than mere background features. Organoid technologies have revolutionized developmental neuroscience, enabling researchers to model human brain development and test hypotheses that would be impossible using animal models alone.
The researchers hope these studies will further our understanding of normal brain development and potentially shed light on the origins of various neurological conditions.
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