Abstract
The development of three-dimensional culture methods has allowed for the study of developing cortical morphology in human cells. This provides a new tool to study the neurodevelopmental consequences of disease-associated mutations. Here, we study the effects of isogenic DISC1 mutation in cerebral organoids. DISC1 has been implicated in psychiatric disease based on genetic studies, including its interruption by a balanced translocation that increases the risk of major mental illness. Isogenic wild-type and DISC1-disrupted human-induced pluripotent stem cells were used to generate cerebral organoids, which were then examined for morphology and gene expression. We show that DISC1-mutant cerebral organoids display disorganized structural morphology and impaired proliferation, which is phenocopied by WNT agonism and rescued by WNT antagonism. Furthermore, there are many shared changes in gene expression with DISC1 disruption and WNT agonism, including in neural progenitor and cell fate markers, regulators of neuronal migration, and interneuron markers. These shared gene expression changes suggest mechanisms for the observed morphologic dysregulation with DISC1 disruption and points to new avenues for future studies. The shared changes in three-dimensional cerebral organoid morphology and gene expression with DISC1 interruption and WNT agonism further strengthens the link between DISC1 mutation, abnormalities in WNT signaling, and neuropsychiatric disease.
Highlights
Modeling human neurodevelopment is a challenging but essential undertaking for addressing the cellular and molecular mechanisms underlying certain psychiatric diseases
Induced pluripotent stem cells have been derived from patients suffering from a variety of psychiatric diseases, and advances in genome engineering allow for efficient introduction and correction of genetic lesions that increase risk for disease
We show that cerebral organoids with DISC1 disruption are morphologically distinct from wild-type organoids
Summary
Modeling human neurodevelopment is a challenging but essential undertaking for addressing the cellular and molecular mechanisms underlying certain psychiatric diseases. A number of differentiation protocols exist for directing stem cells to neuronal and astrocyte fates found along the neuraxis, with both monolayer and three-dimensional culture models available. These complementary methods have the potential to provide insights into the effects of gene disruption on neurodevelopmental processes. Numerous laboratories have optimized monolayer differentiation protocols that efficiently generate neuronal cultures of a variety of fates. The use of these protocols is highly valuable and often essential if consistent and robust phenotypes are to be identified. To study human neurodevelopmental processes in a 3D structure, protocols have been developed to create
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