Researchers at the University of California, Irvine have developed a new method that allows them to engineer lab-grown human brain tissue with defined regional identities. This advance enables scientists to produce organoids—small, three-dimensional tissues grown from human stem cells—that mirror characteristics of either the front or the back of the developing cerebral cortex.
The human brain’s outer layer, the cerebral cortex, is organized into distinct areas, each performing specialized functions like movement, vision, memory, and language. This process, known as “arealization,” is fundamental to the brain’s capabilities and is believed to play a role in certain conditions affecting brain development. Until now, reproducing this specific organization in lab-grown models has presented a significant challenge for scientists.
The UC Irvine-led team published their findings in *Cell Stem Cell*, detailing how they created human neocortical organoids. These organoids were steered to adopt the identity of either a front or a back region, offering a new tool to understand how the human brain develops and what occurs when this process is disrupted in neurodevelopmental disorders.
Momoko Watanabe, Ph.D., assistant professor of anatomy and neurobiology in the UC Irvine School of Medicine and a faculty member of the Sue & Bill Gross Stem Cell Research Center, explained that “By introducing regional identity into these models, we can begin asking questions about development and disease that were difficult to address with conventional organoids.” While ordinary brain organoids replicate many features of developing brain tissue, they typically lack this regional patterning, resulting in a patchwork of random regions rather than clear front or back characteristics.
The UC Irvine team overcame this by exposing developing organoids to carefully selected chemical signals early in their growth. This technique allowed researchers to direct the organoids toward characteristics associated with either the front or the back of the cortex. To confirm these differences, researchers examined over 200,000 individual cells. Their analysis showed that the organoids accurately reproduced molecular characteristics found in different regions of the prenatal human cortex.
This new model was then used to investigate Fragile X Syndrome, a genetic condition and a leading inherited cause of intellectual disability often associated with autism spectrum disorder. The researchers aimed to determine if Fragile X Syndrome affects not only individual brain cells but also the broader developmental patterns that organize cells across the cortex. They found that it did.
Specifically, two proteins crucial for brain development, SOX4 and SOX11, normally appear at different levels in front and back tissue. This difference was consistently observed in organoids grown from donors without the condition. However, in organoids modeling Fragile X Syndrome, this particular difference largely disappeared, indicating a flattening of the usual broad front-to-back patterning. Other research has reported a similar flattening in donated brain tissue from individuals with autism.
The findings do not suggest that disrupted brain patterning causes autism but rather highlight a potential developmental process that can now be studied in a human tissue model with increased spatial detail. The potential applications of this approach extend beyond Fragile X Syndrome, allowing researchers to study how neurological and neurodevelopmental disorders affect different parts of the brain.
By giving organoids defined regional characteristics, scientists can begin to investigate not only what changes in a disorder but also where those changes emerge during development. The platform also contributes to efforts to develop human tissue-based research models that can supplement animal studies, which are limited by differences in human brain development compared to other species. Researchers believe the approach could be used to examine how genetic and environmental factors influence different regions of the developing cortex, potentially leading to new insights into disease mechanisms and therapeutic strategies.
Watanabe’s lab at UC Irvine, which specializes in human brain organoid models to study brain development and neurological disease, is part of a broader interdisciplinary effort. This collaboration spans UC Irvine’s School of Medicine, School of Physical Sciences, Charlie Dunlop School of Biological Sciences, Sue & Bill Gross Stem Cell Research Center, and NSF-Simons Center for Multiscale Cell Fate Research, alongside a collaborator from the University of Pennsylvania. The research received support from organizations including the National Institutes of Health, National Science Foundation, California Institute for Regenerative Medicine, Simons Foundation, and FRAXA Research Foundation.
