Evaluating the Molecular Impact of PTEN Heterozygosity on Cortical Cell Populations via mTOR Signaling in ASD Brain Organoids

The mammalian target of rapamycin (mTOR) signaling pathway plays a crucial role in the human cerebral cortex, which has increased progenitor, neuronal, and glial cell number and diversity compared to other species. Progenitor cells, including the outer radial glia (oRG) and intermediate progenitor cells (IPC), are expanded in the human brain and are vital for appropriately differentiating into mature neuronal and glial cells which establish neural structure. Neural cell growth, differentiation, and morphology are closely linked to the mTOR pathway during brain formation. Disruptions in the mTOR pathway are associated with neurodevelopmental disorders termed “mTORopathies,” highlighting the importance of understanding its mechanism. The mTOR pathway is comprised of two complexes: mTORC1 and mTORC2. The role of mTORC1 in neuronal differentiation is better characterized, while the specific contribution of mTORC2 is less understood. Identifying mTOR-sensitive cell types in the human brain is imperative. Heterozygous mutation in the mTOR pathway gene, PTEN, can lead to comorbid Autism (ASD) and megalencephaly. However, the specific molecular consequences of mTOR and PTEN changes in brain development remain unclear. Human cortical organoids, derived from induced pluripotent stem cells (iPSCs), provide a valuable model to study early neurodevelopment. Organoids enable the study of changes in both typical and atypical human brain development, with various neural cells contributing significantly to brain cell-type diversity. Using cortical organoids derived from patients with ASD and megalencephaly, with a PTEN mutation, could provide insights into the impact on the temporal development of different neural cell types during brain formation.