Summary: A new study has revealed how two morphogens, WNT and Sonic Hedgehog, act as molecular “traffic cops,” directing early human brain development. Using a custom device and stem cell-derived organoids, researchers showed that exposure to these signals for just five days sets gene programs in motion that shape brain regions.
Intriguingly, sensitivity to these morphogens varied between donors and even among cell lines from the same individual, suggesting both genetic and epigenetic influences. The findings highlight the robust yet flexible nature of early brain development and offer new insight into how individual differences emerge at the molecular level.
Key Facts:
- Signal-Driven Development: WNT and Sonic Hedgehog morphogens regulate gene activity that shapes brain structure in just days.
- Personal Variation: Sensitivity to morphogens varied between individuals and even among stem cell lines from the same person.
- Genetic and Epigenetic Impact: Differences stem from both genetic background and post-conception changes.
Source: Yale
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.
Surprisingly, morphogen-elicited gene activity varied among different cell lines derived from a single individual. Other genes involved in cell metabolism fluctuated from one experimental prep to another in the same cell lines, the authors said.
The variable response patterns across donors are likely driven by their genetic background, the authors found. However, variations in the responses to morphogens in stem cell lines from the same donor are likely caused by epigenetic changes or post-conception mutations carried by each line.
Altogether, the findings indicate the fluid nature of brain development across people and even within the same individual.
“It was striking to see that the human brain development can be triggered by a relatively short exposure to two key signals and that it is apparently very robust to variation of gene expression,” Levchenko, who is also director of the Systems Biology Institute at Yale’s West Campus, said.
“This research opens the door to a more compressive modeling and understanding of a key developmental process that can be linked to specific human subjects in a much more precise manner than before.”
Co-lead authors on the paper were Yale’s Soraya Scuderi and Alexandre Jourdon, both associate research scientists at the Child Study Center, and Taeyun Kang, associate research scientist in Levchenko’s lab.
Members of the Systems Biology Institute, the Yale Stem Cell Center, and the Department of Neuroscience contributed to the research.
Funding: The research was primarily funded by the National Institutes of Health and spearheaded by an innovator award from the Yale Kavli Institute for Neuroscience.
About this genetics and neurodevelopment research news
Author: Bess Connolly
Source: Yale
Contact: Bess Connolly – Yale
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Specification of human brain regions with orthogonal gradients of WNT and SHH in organoids reveals patterning variations across cell lines” by Flora Vaccarino et al. Cell Stem Cell
Abstract
Specification of human brain regions with orthogonal gradients of WNT and SHH in organoids reveals patterning variations across cell lines
The repertoire of neurons and their progenitors depends on their location along the antero-posterior and dorso-ventral axes of the neural tube.
To model these axes, we designed the Dual Orthogonal-Morphogen Assisted Patterning System (Duo-MAPS) diffusion device to expose spheres of induced pluripotent stem cells (iPSCs) to concomitant orthogonal gradients of a posteriorizing and a ventralizing morphogen, activating WNT and SHH signaling, respectively.
Comparison with single-cell transcriptomes from the fetal human brain revealed that Duo-MAPS-patterned organoids generated an extensive diversity of neuronal lineages from the forebrain, midbrain, and hindbrain.
WNT and SHH crosstalk translated into early patterns of gene expression programs associated with the generation of specific brain lineages with distinct functional networks.
Human iPSC lines showed substantial interindividual and line-to-line variations in their response to morphogens, highlighting that genetic and epigenetic variations may influence regional specification.
Morphogen gradients promise to be a key approach to model the brain in its entirety.
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