UC Irvine researchers have developed a new method to engineer lab-grown human brain tissue, known as organoids, with a defined regional identity. This advance allows scientists to create organoids that mimic characteristics of either the front or the back of the developing cerebral cortex. The approach, detailed in a study published in *Cell Stem Cell*, could enhance understanding of human brain development and how it is affected in neurodevelopmental disorders.
The human brain’s outer layer, the cerebral cortex, is organized into distinct areas during development, each responsible for different functions such as movement, vision, and memory. This process, called “arealization,” is crucial for brain function and can be disrupted in certain conditions. While brain organoids have become powerful tools for studying human development, they typically form a random patchwork of regions, lacking the organized front-to-back patterning seen in natural development.
The UC Irvine-led team, which included lead author Momoko Watanabe, Ph.D., an assistant professor of anatomy and neurobiology in the UC Irvine School of Medicine, found a way to introduce this organization. By exposing developing organoids to specific chemical signals early in their growth, researchers could guide them to develop characteristics associated with either the front or the back of the cortex. Analysis of over 200,000 individual cells confirmed that these organoids reproduced molecular characteristics similar to those found in different regions of the prenatal human cortex. According to Dr. Watanabe, "By introducing regional identity into these models, we can begin asking questions about development and disease that were difficult to address with conventional organoids."
The team then used this new model to investigate Fragile X syndrome, a genetic condition linked to intellectual disability and autism spectrum disorder. They examined whether the syndrome affected broader developmental patterns beyond individual brain cells. Researchers found that two proteins important for brain development, SOX4 and SOX11, which normally show different levels in front and back tissue, had these differences largely disappear in organoids modeling Fragile X syndrome. This finding aligns with observations in donated brain tissue from individuals with autism, where the gap in SOX4 and SOX11 levels between cortical regions is smaller than expected.
The findings highlight a potential developmental process that can now be investigated in a human tissue model with greater spatial detail. This platform contributes to efforts to develop human tissue-based research models that can supplement animal studies, particularly because human brain development has important distinctions from other species. The researchers suggest the approach could be used to examine how genetic and environmental factors affect different regions of the developing cortex, potentially aiding in the study of disease mechanisms and therapeutic strategies.
The research involved investigators from several UC Irvine departments, including the School of Medicine, School of Physical Sciences, Charlie Dunlop School of Biological Sciences, Sue & Bill Gross Stem Cell Research Center, and the NSF-Simons Center for Multiscale Cell Fate Research.
