A groundbreaking study led by Yale researchers has uncovered how two crucial morphogens, WNT and Sonic Hedgehog, function as molecular "traffic cops" during the early stages of human brain development. This research, which utilized a custom device and stem cell-derived organoids, demonstrates that exposure to these signaling molecules for just five days activates gene programs essential for the formation of various brain regions. The findings offer significant insights into the intricate processes governing early brain development and how individual differences arise at a molecular level.
The study highlights how the morphogens WNT and Sonic Hedgehog regulate the activation of gene activity critical to shaping brain structure in a remarkably short timeframe. Specifically, the researchers found that sensitivity to these morphogens varied not only among different individuals but also between different cell lines derived from the same person. This variability underscores the complex interplay of genetic and epigenetic factors influencing brain development.
Flora Vaccarino, the Harris Professor in the Child Study Center at the Yale School of Medicine and co-senior author of the study, emphasized the importance of these findings. "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," Vaccarino stated. The research, published on May 1 in the journal Cell Stem Cell, was co-led by Andre Levchenko, the John C. Malone Professor of Biomedical Engineering at Yale.
The team developed a specialized device known as Duo-MAPs, which allowed them to expose organoids derived from human stem cells to the two key morphogens. The WNT morphogen plays a critical role along the posterior-anterior axis of the developing central nervous system, while Sonic Hedgehog operates along the ventro-dorsal axis. Their combined effects over just five days were found to regulate gene activity that ultimately determines the structure and cell composition of nearly all brain regions.
Intriguingly, the high-throughput analysis enabled by the Duo-MAPs device revealed significant differences in gene activity between organoids derived from different donors and stem cell lines. For instance, some organoids exhibited heightened sensitivity to WNT morphogen, with activated genes concentrated in the hindbrain, while others demonstrated lower sensitivity, shifting gene activity towards the developing cortex in the frontal brain areas. Similarly, variations in sensitivity to Sonic Hedgehog resulted in distinct gene activity patterns in different brain regions, such as the basal ganglia and cerebellum.
The study concluded that the variability in morphogen responses across different donors likely stems from their unique genetic backgrounds. In contrast, the differences observed in stem cell lines derived from the same individual are believed to result from epigenetic changes or post-conception mutations. This fluid nature of brain development highlights the complexity of how individual differences emerge at both genetic and molecular levels.
"It was striking to see that human brain development can be triggered by a relatively short exposure to these key signals, and that it is remarkably robust to variations in gene expression," Levchenko remarked. This research paves the way for more comprehensive modeling and understanding of brain development processes, potentially allowing for more precise connections to specific human subjects than ever before.
The study's co-lead authors included Yale's Soraya Scuderi and Alexandre Jourdon, along with Taeyun Kang. Significant contributions were made by members of the Systems Biology Institute, Yale Stem Cell Center, and the Department of Neuroscience. The research was primarily funded by the National Institutes of Health and supported by an innovator award from the Yale Kavli Institute for Neuroscience.
This innovative research sheds light on the fundamental mechanisms of early brain development and emphasizes the importance of both genetic and epigenetic factors. As researchers continue to explore the complexities of brain development, these findings hold promise for advancing our understanding of neurodevelopmental disorders and individual differences in brain function.
