Biological Psychiatry Global Open Science (Sep 2024)
Using Organoids to Model Sex Differences in the Human Brain
- Adam Pavlinek,
- Dwaipayan Adhya,
- Alex Tsompanidis,
- Varun Warrier,
- Anthony C. Vernon,
- Madeline Lancaster,
- Jonathan Mill,
- Deepak P. Srivastava,
- Simon Baron-Cohen,
- Simon Baron-Cohen,
- Carrie Allison,
- Varun Warrier,
- Alex Tsompanidis,
- Dwaipayan Adhya,
- Rosie Holt,
- Paula Smith,
- Tracey Parsons,
- Joanna Davis,
- Matthew Hassall,
- Daniel H. Geschwind,
- Alexander EP. Heazell,
- Jonathan Mill,
- Alice Franklin,
- Rosie Bamford,
- Jonathan Davies,
- Matthew E. Hurles,
- Hilary C. Martin,
- Mahmoud Mousa,
- David H. Rowitch,
- Kathy K. Niakan,
- Graham J. Burton,
- Fateneh Ghafari,
- Deepak P. Srivastava,
- Lucia Dutan-Polit,
- Adam Pavlinek,
- Madeline A. Lancaster,
- Ilaria Chiaradia,
- Tal Biron-Shental,
- Lidia V. Gabis
Affiliations
- Adam Pavlinek
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; MRC Centre for Neurodevelopmental Disorders, King’s College London, London, United Kingdom
- Dwaipayan Adhya
- Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Address correspondence to Dwaipayan Adhya, Ph.D.
- Alex Tsompanidis
- Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
- Varun Warrier
- Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom; Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
- Anthony C. Vernon
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; MRC Centre for Neurodevelopmental Disorders, King’s College London, London, United Kingdom
- Madeline Lancaster
- MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
- Jonathan Mill
- Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
- Deepak P. Srivastava
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; MRC Centre for Neurodevelopmental Disorders, King’s College London, London, United Kingdom
- Simon Baron-Cohen
- Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
- Simon Baron-Cohen
- Autism Research Centre, University of Cambridge, Cambridge, United Kingdom
- Carrie Allison
- Autism Research Centre, University of Cambridge, Cambridge, United Kingdom
- Varun Warrier
- Autism Research Centre, University of Cambridge, Cambridge, United Kingdom
- Alex Tsompanidis
- Autism Research Centre, University of Cambridge, Cambridge, United Kingdom
- Dwaipayan Adhya
- Autism Research Centre, University of Cambridge, Cambridge, United Kingdom
- Rosie Holt
- Autism Research Centre, University of Cambridge, Cambridge, United Kingdom
- Paula Smith
- Autism Research Centre, University of Cambridge, Cambridge, United Kingdom
- Tracey Parsons
- Autism Research Centre, University of Cambridge, Cambridge, United Kingdom
- Joanna Davis
- Autism Research Centre, University of Cambridge, Cambridge, United Kingdom
- Matthew Hassall
- Autism Research Centre, University of Cambridge, Cambridge, United Kingdom
- Daniel H. Geschwind
- UCLA, Los Angeles, California
- Alexander EP. Heazell
- Tommy’s Maternal and Fetal Research Centre, University of Manchester, Manchester, United Kingdom
- Jonathan Mill
- University of Exeter Medical School, College of Medicine & Health, University of Exeter, Exeter, United Kingdom
- Alice Franklin
- University of Exeter Medical School, College of Medicine & Health, University of Exeter, Exeter, United Kingdom
- Rosie Bamford
- University of Exeter Medical School, College of Medicine & Health, University of Exeter, Exeter, United Kingdom
- Jonathan Davies
- University of Exeter Medical School, College of Medicine & Health, University of Exeter, Exeter, United Kingdom
- Matthew E. Hurles
- Wellcome Trust Sanger Institute, Hinxton, United Kingdom
- Hilary C. Martin
- Wellcome Trust Sanger Institute, Hinxton, United Kingdom
- Mahmoud Mousa
- Wellcome Trust Sanger Institute, Hinxton, United Kingdom
- David H. Rowitch
- Department of Pediatrics, University of Cambridge, Cambridge, United Kingdom
- Kathy K. Niakan
- Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom
- Graham J. Burton
- Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom
- Fateneh Ghafari
- Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom
- Deepak P. Srivastava
- MRC Centre for Neurodevelopmental Disorders, King’s College London, London, United Kingdom
- Lucia Dutan-Polit
- MRC Centre for Neurodevelopmental Disorders, King’s College London, London, United Kingdom
- Adam Pavlinek
- MRC Centre for Neurodevelopmental Disorders, King’s College London, London, United Kingdom
- Madeline A. Lancaster
- MRC Laboratory of Molecular Biology, University of Cambridge, Cambridge, United Kingdom
- Ilaria Chiaradia
- MRC Laboratory of Molecular Biology, University of Cambridge, Cambridge, United Kingdom
- Tal Biron-Shental
- Department of Obstetrics and Gynecology, Meir Medical Center, Israel
- Lidia V. Gabis
- Child Development Division, Maccabi Health Services, Israel
- Journal volume & issue
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Vol. 4,
no. 5
p. 100343
Abstract
Sex differences are widespread during neurodevelopment and play a role in neuropsychiatric conditions such as autism, which is more prevalent in males than females. In humans, males have been shown to have larger brain volumes than females with development of the hippocampus and amygdala showing prominent sex differences. Mechanistically, sex steroids and sex chromosomes drive these differences in brain development, which seem to peak during prenatal and pubertal stages. Animal models have played a crucial role in understanding sex differences, but the study of human sex differences requires an experimental model that can recapitulate complex genetic traits. To fill this gap, human induced pluripotent stem cell–derived brain organoids are now being used to study how complex genetic traits influence prenatal brain development. For example, brain organoids from individuals with autism and individuals with X chromosome–linked Rett syndrome and fragile X syndrome have revealed prenatal differences in cell proliferation, a measure of brain volume differences, and excitatory-inhibitory imbalances. Brain organoids have also revealed increased neurogenesis of excitatory neurons due to androgens. However, despite growing interest in using brain organoids, several key challenges remain that affect its validity as a model system. In this review, we discuss how sex steroids and the sex chromosomes each contribute to sex differences in brain development. Then, we examine the role of X chromosome inactivation as a factor that drives sex differences. Finally, we discuss the combined challenges of modeling X chromosome inactivation and limitations of brain organoids that need to be taken into consideration when studying sex differences.
