TY - JOUR
T1 - Using Organoids to Model Sex Differences in the Human Brain
AU - APEX Consortium
AU - Pavlinek, Adam
AU - Adhya, Dwaipayan
AU - Tsompanidis, Alex
AU - Warrier, Varun
AU - Baron-Cohen, Simon
AU - Allison, Carrie
AU - Holt, Rosie
AU - Smith, Paula
AU - Parsons, Tracey
AU - Davis, Joanna
AU - Hassall, Matthew
AU - Geschwind, Daniel H.
AU - Heazell, Alexander EP
AU - Mill, Jonathan
AU - Franklin, Alice
AU - Bamford, Rosie
AU - Davies, Jonathan
AU - Hurles, Matthew E.
AU - Martin, Hilary C.
AU - Mousa, Mahmoud
AU - Rowitch, David H.
AU - Niakan, Kathy K.
AU - Burton, Graham J.
AU - Ghafari, Fateneh
AU - Srivastava, Deepak P.
AU - Dutan-Polit, Lucia
AU - Lancaster, Madeline A.
AU - Chiaradia, Ilaria
AU - Biron-Shental, Tal
AU - Gabis, Lidia V.
AU - Vernon, Anthony C.
AU - Lancaster, Madeline
N1 - Publisher Copyright:
© 2024
PY - 2024/7/1
Y1 - 2024/7/1
N2 - 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.
AB - 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.
KW - Autism
KW - Brain organoids
KW - Sex chromosomes
KW - Sex differences
KW - Steroids
KW - X chromosome inactivation
UR - http://www.scopus.com/inward/record.url?scp=85198005451&partnerID=8YFLogxK
U2 - 10.1016/j.bpsgos.2024.100343
DO - 10.1016/j.bpsgos.2024.100343
M3 - Review article
AN - SCOPUS:85198005451
SN - 2667-1743
VL - 4
JO - Biological Psychiatry Global Open Science
JF - Biological Psychiatry Global Open Science
IS - 5
M1 - 100343
ER -