Year: 2026
Type: article
Abstract: The human neocortex exhibits characteristic regional patterning (arealization) critical for higher-order cognitive function. Disrupted arealization is implicated in neurodevelopmental disorders (NDDs), but current neocortical organoid models largely fail to recapitulate this patterning, limiting mechanistic understanding. We establish a straightforward method for generating arealized organoids through short-term early exposure to anterior or posterior morphogens. These treatments created distinct anteroposterior (AP) signaling centers, supporting long-lasting polarization validated by spatial and single-cell RNA sequencing, which revealed area-specific molecular signatures matching the prenatal human cortex. To demonstrate utility, we modeled fragile X syndrome (FXS) in organoids with distinct AP identities. FXS organoids showed disrupted expression gradients along the AP axis, consistent with alterations in autism spectrum disorder, demonstrating how regional patterning defects may contribute to NDD pathology. Together, our study provides a robust platform for generating neocortical organoids with AP molecular signatures and highlights the importance of modeling NDDs using experimental platforms with neuroanatomic specificity.
Source: Cell stem cell
Authors: Yuan-Chen Tsai, Hajime Ozaki, Axel A. Almet, Isabel Fleming, Caihao Nie, Songhao Luo, Xinyi Wang, Kaori Shiraiwa, Matthew Jung Min Noh, Sunnyana Trejo, Bret Kiyoshi Sugita, Jiya Dalal, Ruben Alberto Gonzalez, Briana De Jesus, Nate Branco, Gregory Li-Min Chen, Michael J. Gandal, Qing Nie, Momoko Watanabe
Institutions: University of California, Irvine, University of Pennsylvania
Language: English
Subfield: Developmental Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $10,400
Funders: National Science Foundation, FRAXA Research Foundation, Simons Foundation, California Institute for Regenerative Medicine, Simons Foundation Autism Research Initiative, National Institutes of Health, National Institute of Mental Health, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, School of Medicine, University of California, Irvine
Awards: G1454206734, RECODE: Functional characterization of human skin organoids, G1875159677, G2318624699, CIRM Scholars Comprehensive Research Training Program, G3212921093, G3658124931, G4635388232, G5398183627, G6037676544, RECODE: Spatial engineering of morphogens for the reproducible formation of cortical organoids with arealization, Research Mentorship Program in Regenerative Medicine Careers for a Diverse Undergraduate Student Body, G6575361694, G6791967163, G7425150905, Bridges to Stem Cell Research and Therapy: A Talent Development Program for Training Diverse Undergraduates for Careers in Regenerative Medicine, Training Program in Stem Cell Translational Medicine for Neurological Disorders, G986754019
OpenAlex ID: W7203838458