UCLA scientists have created one of the first cell-resolution molecular maps detailing how Down syndrome affects prenatal brain development in humans. This is a resource that has the potential to resolve long-standing contradictions in the field and lay the foundation for future treatment strategies.
This study scienceanalyzed more than 100,000 nuclei from human prenatal neocortical samples collected from 26 genotyped donors between 13 and 23 weeks of gestation. This period is the only period in which all the cortical neurons that a person will have for the rest of their lives are generated. This finding suggests that Down syndrome disrupts the developmental order of that process, causing changes that may help explain later differences in cognition, learning, and sensory processing.
There’s a new level of detail here that didn’t exist before. For the first time, it is now possible to systematically understand what is happening in the developing brains of people with Down syndrome. ”
Luis de la Torre Ubieta, senior author of the study and member of UCLA’s Eli Edith Broad Center for Regenerative Medicine and Stem Cell Research
fill a critical gap
The field of Down syndrome research has historically focused on two areas: the adult brain and the relationship between Down syndrome and neurodegeneration. This association is surprising, as the majority of people with Down syndrome usually develop Alzheimer’s disease by their 60s.
Despite clear indicators that Down syndrome is a developmental disorder, such as reduced brain volume detectable by MRI and cognitive differences evident as early as six months to one year of age, what has remained largely unexplored is how Down syndrome shapes the developing brain itself.
“No one has used single-cell genomics to directly look at the developing human brain with Down syndrome,” said de la Torre Ubieta, assistant professor of psychiatry and biobehavioral sciences. “Mouse and in vitro models are important tools, but they do not accurately represent what is happening in the human brain. In fact, they give different results and cause confusion in the field.”
These discrepancies are partially due to differences in how mouse and human brains develop and the fact that in vitro models do not fully represent all cell types and tissues present in the brain.
De la Torre Ubieta said this new study could serve as a resource for that gold standard.
Disruption of developmental order and its effects on brain size
Prenatal neocortical development typically follows a strictly coordinated sequence. Progenitor cells (brain stem cells) must first divide repeatedly to expand their pool and build a sufficient base for all future neurons. Only then do they begin to differentiate into neurons, starting with deep cell types and progressing towards upper layer cells in a carefully timed sequence.
In Down syndrome, this order appears to be disrupted. The study found that progenitor cells appear to start producing neurons prematurely, depleting their own pool and skewing the balance of the types of neurons produced. Specifically, the researchers observed a relative increase in upper intracerebral neurons and a decrease in deep corticothalamic neurons.
These two cell populations play fundamentally different roles. CT neurons project outward from the cortex and connect to brain structures and the spinal cord to control sensation and movement. IT neurons are wired within the cortex, connecting the two hemispheres and contributing to information processing. This finding provides a new hypothesis about how early developmental changes contribute to the cognitive profile of symptoms.
The discovery also provides a new answer to a long-standing question in the field: Why do people with Down syndrome tend to have smaller brains? Previous theories focused on increased cell death rates. Current studies show less evidence of widespread neuronal cell death and instead point to depletion of the progenitor cell pool.
A system-level view of system-level failures
In this study, we employed paired mononuclear multiomics, a technique that measures both gene expression and chromatin accessibility in the same individual cells. Chromatin accessibility reveals which regions of the genome are open and active, and enhancers and promoters, which regulate gene expression, provide a layer of information that simply switches genes on or off.
By combining these two readouts, the researchers were able to reconstruct not only a snapshot of which cells are present, but also the regulatory programs that guide their fate and how those programs are disrupted in Down syndrome. Systems-level approaches also reveal changes in cellular metabolism and in the way the vasculature interacts with the developing nervous system, both of which may promote neuron generation.
Impact beyond Down syndrome
The importance of this research extends beyond Down syndrome. The researchers specifically examined the overlap between the molecular disruptions they identified and genetic risk signatures associated with other neurodevelopmental and neuropsychiatric conditions, such as autism, epilepsy, and developmental delays. They found substantial convergence, particularly in the gene regulatory networks governing the specification of IT and CT neurons.
“Down syndrome may serve as a model for understanding intellectual and neuropsychiatric disorders more broadly,” de la Torre Ubieta said. “We also aim to uncover the common biology underlying these symptoms, because the mechanisms are often still unknown.”
Two papers, one story
This publication was co-published and published in the same issue as a related paper by researchers at the University of Wisconsin-Madison. science. While the UCLA study focuses on the prenatal period, the Wisconsin team is examining the brain after birth, studying Down syndrome from about 1 to 5 years of age.
When the two groups shared their preliminary findings, they discovered striking similarities. Many of the changes the UCLA team identified before birth appear to persist into early childhood.
Together, the two papers provide a continuous molecular look at brain development in people with Down syndrome from mid-pregnancy to infancy, a previously unavailable source of information that the researchers hope will inform their field for years to come.
Foundation for future treatments
Although the researchers are careful to stress that their findings do not imply short-term clinical applications, the study provides the clearest picture to date of the cellular and molecular events that differentiate the brain in Down syndrome during development, and provides a framework for identifying future therapeutic targets.
“We are finding targets that could potentially become practical in the future if we create drugs for specific pathways,” de la Torre Ubieta said. “And based on this, we could think of gene therapies that suppress the expression of specific drivers and bring development closer to normal processes.”
UCLA authors Celine K. Vuong and Alexis Weber led the work, along with Patrick Song, Yujen Chen, Jordan Payer, Shahab Yunesi, Angelo Salinda, Daniel Gomez, Gabriela Rivas, Abril Morales, Bec Shafi, Pan Jiang, Suzanne Nichterwitz, Li Qi, Nolan T. Fernandez, Emily Friedman, Daniel H. Geschwind and William E. Rowley. Nana Mataba, Michael I. Love, Michael J. Gandal, and Jason L. Stein contributed to this research.
This research was supported by the National Institute of Child Health and Development, the National Institute of Mental Health, the UCLA Broad Stem Cell Research Center including a Rose Hills Foundation Innovator Grant and a Postdoctoral Training Grant, the UCLA Health Johnson Comprehensive Cancer Center and the UCLA Broad Stem Cell Research Center Abron Scholars Program, the California Institute for Regenerative Medicine and the National Institutes of Health Biomedical Big Data Training Program.
sauce:
University of California, Los Angeles Health Sciences
Reference magazines:
Vuong, C.K. Others. (2026). Single-cell multiohmic analysis identifies molecular and gene regulatory mechanisms that are dysregulated in neocortical development in Down syndrome. science. DOI: 10.1126/science.aea1259. https://www.science.org/doi/10.1126/science.aea1259
