How molecular traffic cops guide development of the human brain
2025-05-01T15:00:00Z
A new Yale study offers new insight into how morphogens help regulate the development of stem cells into specialized brain cells.
Just a few weeks after conception, stem cells are already orchestrating the future structure of the human brain. A new Yale-led study shows that, early in development, molecular “traffic cops” known as morphogens regulate the activation of gene programs that initiate stem cells’ differentiation into more specialized brain cells.
The Yale team found that sensitivity to these signaling morphogens can vary not only between stem cells from different donors, but between stem cells derived from the same individual.
“This is a new chapter in understanding how we develop and how development can be influenced by genomic changes between people and by epigenetic modifications within individuals,” said Flora Vaccarino, the Harris Professor in the Child Study Center at the Yale School of Medicine (YSM) and co-senior author of the research, published May 1 in the journal Cell Stem Cell.
The team, led by Vaccarino and co-senior author Andre Levchenko, the John C. Malone Professor of Biomedical Engineering at the Yale School of Engineering & Applied Science and at YSM, developed a device called Duo-MAPs, which allowed them to expose organoids derived from human stem cells to two crucial morphogens naturally present within the developing brain. The WNT morphogen, active along the posterior-anterior (bottom to top) axis of the nascent central nervous system, interacts with the Sonic Hedgehog morphogen, which operates along ventro-dorsal (front to back) axis of developing nervous system.
Together, the location and concentrations of the two morphogens over just 5 days regulated the gene activity that determined the eventual structure and cell composition of almost all brain regions, the researchers found.
Intriguingly, the high-throughput analysis enabled by the device showed distinct differences in the two morphogens’ gene activity in organoids derived from different individuals and different stem cell lines. For instance, organoids from some stem cell lines showed higher sensitivity to the WNT morphogen and the activated genes were concentrated towards the bottom of the brain where the hindbrain develops.
Other lines showed lower sensitivity to WNT and activity shifted toward anterior or frontal brain areas, such as the developing cortex. Similarly, stem cell lines more sensitive to Sonic Hedgehog showed higher gene activity in the developing basal ganglia, while stem cells less sensitive to the morphogen had a greater gene response in the developing cerebellum. The morphogen-response genes that were most variable among different donors involved functions such as immune response, other experiments showed.
Auto-posted from news source
About The Author
