Intellectual disability (ID) and epilepsy are now known to result from many defects including cortical malformations, miswired neuronal circuits and perturbations of synaptic function. Genetic approaches in combination with magnetic resonance imaging (MRI) has allowed a better diagnosis and classification of these disorders, including those corresponding to malformations of cortical development (MCD) associated with gyral abnormalities, such as type 1 lissencephaly, pachygyria, and polymicrogyria (PMG). Over the past few years, the importance of cytoskeletal components in cellular processes crucial for cortical development has emerged from a body of functional and genetic data. This is typified by the LIS1 and DCX genes, which both encode proteins involved in microtubule (MT) homeostasis, and if mutated result in cerebral cortex developmental disorders. The recent discoveries by partners of this proposal and others, of patients with lissencephaly/pachygyria spectrum and polymicrogyria carrying mutations in TUBA1A, TUBB2B, TUBB3 and TUBA8 further support this view and raise interesting questions about the specific roles played by certain tubulin isotypes during the development of the cortex. The aim of this proposal is to investigate the genetic basis and pathophysiological mechanisms that underlie MCD with a focus on the tubulins and their core components. Specifically we will pursue the following objectives: (1) The identification of new genes that cause cortical malformation disorders by whole exome sequencing and targeted next generation sequencing in order to provide a comprehensive overview of the genetic causes and the spectrum of cortical malformation disorders associated with gyral abnormalities; (2) Characterize the roles of TUBA1A, TUBB2B, and TUBB3 during cortical development by complementary in vitro and in vivo approaches, including the generation and characterization of novel mouse models.