Thalamocortical organoids enable in vitro modeling of 22q11.2 microdeletion associated with neuropsychiatric disorders

David Shin; Chang N Kim; Jayden Ross; Kelsey M Hennick; Sih-Rong Wu; Neha Paranjape; Rachel Leonard; Jerrick C Wang; Matthew G Keefe; Bryan J Pavlovic; Kevin C Donohue; Clara Moreau; Emilie M Wigdor; H Hanh Larson; Denise E Allen; Cathryn R Cadwell; Aparna Bhaduri; Galina Popova; Carrie E Bearden; Alex A Pollen; Sebastien Jacquemont; Stephan J Sanders; David Haussler; Arun P Wiita; Nicholas A Frost; Vikaas S Sohal; Tomasz J Nowakowski

doi:10.1016/j.stem.2024.01.010

Thalamocortical organoids enable in vitro modeling of 22q11.2 microdeletion associated with neuropsychiatric disorders

Cell Stem Cell. 2024 Mar 7;31(3):421-432.e8. doi: 10.1016/j.stem.2024.01.010. Epub 2024 Feb 20.

Authors

David Shin¹, Chang N Kim¹, Jayden Ross¹, Kelsey M Hennick¹, Sih-Rong Wu¹, Neha Paranjape², Rachel Leonard¹, Jerrick C Wang¹, Matthew G Keefe¹, Bryan J Pavlovic³, Kevin C Donohue⁴, Clara Moreau⁵, Emilie M Wigdor⁶, H Hanh Larson⁷, Denise E Allen¹, Cathryn R Cadwell⁸, Aparna Bhaduri⁹, Galina Popova¹, Carrie E Bearden¹⁰, Alex A Pollen³, Sebastien Jacquemont¹¹, Stephan J Sanders¹², David Haussler¹³, Arun P Wiita¹⁴, Nicholas A Frost¹⁵, Vikaas S Sohal⁴, Tomasz J Nowakowski¹⁶

Affiliations

¹ Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94158, USA.
² Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA.
³ Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
⁴ Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94158, USA.
⁵ Sainte Justine Research Center, University of Montréal, 3175 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1C5, Canada; Imaging Genetics Center, Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
⁶ Institute of Developmental and Regenerative Medicine, University of Oxford, Headington, Oxford OX3 7TY, UK.
⁷ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA.
⁸ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁹ Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁰ Integrative Center for Neurogenetics, Semel Institute for Neuroscience and Human Behavior, Departments of Psychiatry and Biobehavioral Sciences and Psychology, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90095, USA.
¹¹ Sainte Justine Research Center, University of Montréal, 3175 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1C5, Canada.
¹² Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94158, USA; Institute of Developmental and Regenerative Medicine, University of Oxford, Headington, Oxford OX3 7TY, UK.
¹³ UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA 95060, USA; Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA; Howard Hughes Medical Institute, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
¹⁴ Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94107, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158.
¹⁵ Department of Neurology, University of Utah, Salt Lake City, UT 84108, USA.
¹⁶ Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: [email protected].

PMID: 38382530
PMCID: PMC10939828 (available on 2025-03-07)
DOI: 10.1016/j.stem.2024.01.010

Abstract

Thalamic dysfunction has been implicated in multiple psychiatric disorders. We sought to study the mechanisms by which abnormalities emerge in the context of the 22q11.2 microdeletion, which confers significant genetic risk for psychiatric disorders. We investigated early stages of human thalamus development using human pluripotent stem cell-derived organoids and show that the 22q11.2 microdeletion underlies widespread transcriptional dysregulation associated with psychiatric disorders in thalamic neurons and glia, including elevated expression of FOXP2. Using an organoid co-culture model, we demonstrate that the 22q11.2 microdeletion mediates an overgrowth of thalamic axons in a FOXP2-dependent manner. Finally, we identify ROBO2 as a candidate molecular mediator of the effects of FOXP2 overexpression on thalamic axon overgrowth. Together, our study suggests that early steps in thalamic development are dysregulated in a model of genetic risk for schizophrenia and contribute to neural phenotypes in 22q11.2 deletion syndrome.

Keywords: 22q11 microdeletion; DiGeorge syndrome; neurodevelopmental disorders; organoid; thalamocortical; velocardiofacial syndrome.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

DiGeorge Syndrome* / genetics
DiGeorge Syndrome* / psychology
Humans
Phenotype
Schizophrenia* / genetics

Abstract

Publication types

MeSH terms

Grants and funding