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Mammalian development involves complicated cell morphogenesis and interactions between transcription factors and signaling molecules. The PI3K-AKT-MTOR pathway is one such central intracellular signaling pathway, crucial for cell growth and metabolism. Activating mutations in this pathway have long been linked to cancer. Strongly activating PI3K mutations, found most commonly in cancer, also result in severe brain overgrowth and dysplasia; and can often cause intellectual disabilities, autism, hydrocephalus and intractable epilepsy. I will present my postdoctoral work that identified basic cellular mechanisms and critical developmental periods behind PI3K-related brain overgrowth and dysplasia in conditional mouse mutants. In addition, I will discuss new small-molecule drug therapies that suppressed seizure, cortical dysplasia and developmental hydrocephalus in our models, thus creating promising new therapeutic avenues for such comorbidities. |