Morphogen-guided neocortical organoids with anteroposterior areal identity
5 affiliations
- 1Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA
- 2Department of Mathematics, School of Physical Sciences, University of California, Irvine, Irvine, CA 92697, USA; NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA 92697, USA
- 3Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- 4Department of Mathematics, School of Physical Sciences, University of California, Irvine, Irvine, CA 92697, USA; NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA 92697, USA; Department of Systems Biology, School of Biological Sciences, University of California, Irvine, Irvine, CA 92697, USA
- 5Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA; Sue & Bill Gross Stem Cell Research Center, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: [email protected]
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.
Related
- Spatial engineering of posterior signaling centers in cerebral organoids via controlled morphogen exposure within hydrogels
- CHACAM: a cell-cell interaction-guided hierarchical attention model for high-precision cell identity annotation of scRNA-seq data in early C. elegans embryogenesis
- Ultrastructurally planar growth cones during neocortical axon navigation
- Regulation of morphogen signaling pathways by recurrent hypermotif circuits
- Temperature scaling of developmental tempo reveals reaction-dominated morphogen patterning
BibTeX
@article{tsai2026morphogenguided,
title = {{Morphogen-guided neocortical organoids with anteroposterior areal identity}},
author = {Yuan‐Chen Tsai and Hajime Ozaki and Axel A. Almet and Isabel Fleming and Caihao Nie and Songhao Luo and Xinyi Wang and Kaori Shiraiwa and Matthew Jung Min Noh and Sunnyana Trejo and Bret Kiyoshi Sugita and Jiya Dalal and Ruben Alberto Gonzalez and Briana De Jesus and Nate Branco and Gregory Li-Min Chen and Michael J. Gandal and Qing Hua Nie and Momoko Watanabe},
journal = {Cell stem cell},
year = {2026},
month = aug,
doi = {10.1016/j.stem.2026.07.014},
url = {https://doi.org/10.1016/j.stem.2026.07.014},
note = {CC BY},
}
RIS
TY - JOUR
TI - Morphogen-guided neocortical organoids with anteroposterior areal identity
AU - Yuan‐Chen Tsai
AU - Hajime Ozaki
AU - Axel A. Almet
AU - Isabel Fleming
AU - Caihao Nie
AU - Songhao Luo
AU - Xinyi Wang
AU - Kaori Shiraiwa
AU - Matthew Jung Min Noh
AU - Sunnyana Trejo
AU - Bret Kiyoshi Sugita
AU - Jiya Dalal
AU - Ruben Alberto Gonzalez
AU - Briana De Jesus
AU - Nate Branco
AU - Gregory Li-Min Chen
AU - Michael J. Gandal
AU - Qing Hua Nie
AU - Momoko Watanabe
PY - 2026
DA - 2026/08/20
JO - Cell stem cell
DO - 10.1016/j.stem.2026.07.014
UR - https://doi.org/10.1016/j.stem.2026.07.014
AB - 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.
SN - 1875-9777
SN - 1934-5909
ER -