UC San Diego

Disease modeling for neurodevelopmental disorders has long been a challenging endeavor, necessitating innovative approaches to understand the underlying mechanisms. Traditional animal models, while informative, often fail to fully capture the intricacies of human brain development and associated diseases. FOXG1 syndrome, caused by mutations in the Forkhead box protein G1 (FOXG1) gene and characterized by forebrain developmental abnormalities, represents one such disorder with a range of neurological symptoms including motor deficits, intellectual retardation, and seizures. In recent years, cortical brain organoid models derived from human pluripotent stem cells have emerged as a revolutionary tool in neuroscience research, providing a three-dimensional representation of the human brain. These organoids exhibit structural and functional resemblance to developing brains, encompassing the formation of diverse cell types and the establishment of functional networks. In this study, we were successfully able to develop a cortical organoid model using both healthy and patient derived cell lines for investigating FOXG1 syndrome, with the patient lines accurately reproducing the microcephaly phenotype observed in FOXG1 syndrome We explored strategies to enhance the cortical identity of the model using Wingless/Integrated pathway (WNT pathway) inhibition, achieving promising results. Furthermore, we successfully recapitulated neural tube development by constructing a single rosette organoid, thereby increasing its biomimetic properties. Our findings highlight the potential of cortical organoids as powerful tools for studying human neurodevelopment and neurodevelopmental disorders, offering new avenues for understanding disease pathogenesis and facilitating the development of targeted therapeutic interventions.