Shared effects of DISC1 disruption and elevated WNT signaling in human cerebral organoids

<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>DISC1</jats:italic> mutation in cerebral organoids. <jats:italic>DISC1</jats:italic> 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 <jats:italic>DISC1</jats:italic>-disrupted human-induced pluripotent stem cells were used to generate cerebral organoids, which were then examined for morphology and gene expression. We show that <jats:italic>DISC1</jats:italic>-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 <jats:italic>DISC1</jats:italic> 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 <jats:italic>DISC1</jats:italic> disruption and points to new avenues for future studies. The shared changes in three-dimensional cerebral organoid morphology and gene expression with <jats:italic>DISC1</jats:italic> interruption and WNT agonism further strengthens the link between <jats:italic>DISC1</jats:italic> mutation, abnormalities in WNT signaling, and neuropsychiatric disease.</jats:p>