The mTORC1 signaling cascade provides regulatory control of protein translation, cell differentiation, and cell growth. Mutations in the mTORC1 inhibitory proteins TSC1 and TSC2 cause Tuberous Sclerosis Complex, an autosomal dominant disorder characterized by epilepsy and cognitive disability. Mutations in STRADα, an upstream activator of TSC2, give rise to Pretzel Syndrome, a neurodevelopmental disorder characterized by epilepsy and psychomotor retardation. We show that loss of STRADα function in vitro and in vivo is associated with enhanced cell size, aberrant nuclear localization of the kinase LKB1, and abnormal neuronal lamination as a consequence of aberrant mTORC1 signaling. We further show in human brain specimens and cultured cells in vitro that sporadic and syndromic type II Focal Cortical Dysplasias exhibit aberrant mTORC1 activation in association with persistent expression of stem cell markers. Therefore, mTORC1 hyperactivation may be a unifying feature of neurodevelopmental disorders characterized by epilepsy, autism, and cognitive disability and pharmacological inhibitors of mTOR may prove to be therapeutically beneficial in the treatment of these disorders
