Developmental disorders of the nervous system are amongst the most catastrophic illnesses, and those effecting the assembly and function of the cerebral cortex, including epilepsy, schizophrenia, and autism are particularly devastating and often refractory to treatment. A common feature uniting these disparate neurologic and psychiatric disorders is the malfunction of inhibitory cortical circuitry and a shared neurodevelopmental etiology. One significant source of pathological vulnerability occurs during embryonic development, when cortical interneurons migrate from their place of origin in the ventral forebrain to the overlying cerebral cortex. Migratory cortical interneurons sense and respond to numerous guidance cues in order to make correct navigational decisions as they exit the ventral forebrain, enter the cerebral cortex, travel in streams of migratory interneurons, and finally infiltrate the cortical plate and target discrete cortical laminae. Molecular mechanisms allowing cortical interneurons to make correct decisions along their migratory paths are ill defined. Our recently published and ongoing work indicate novel and surprising roles for the ubiquitous c-Jun-N- terminal kinase (JNK) signaling pathway in orchestrating key navigational decisions made by migrating cortical interneurons, including those enabling their entrance into the cerebral cortex, selection of migratory streams, and correct timing of migratory stream departure. These observations lead to our central hypothesis that precise spatial and temporal control of JNK activity enables appropriate construction of cortical circuitry by facilitating the guided migration of cortical interneurons. The objective of our proposal is to elucidate cellular and molecular mechanisms eliciting dynamic changes in cellular behavior that are essential for orienting neuronal migration in response to extracellular guidance cues. We propose to: 1) Determine how JNK activity regulates nucleokinesis, branching, and subcellular localization of the microtubule regulatory protein doublecortin (Dcx) during cortical interneuron migration, 2) Evaluate the functional significance of JNK-Dcx interactions during guided migration and differentiation of cortical interneurons, and 3) Determine how intracellular JNK activity controls timing of migratory stream exit and intracortical dispersion. We combine mouse genetics with powerful imaging techniques and novel molecular tools to investigate the cellular and molecular biology of cortical interneuron migration in situ. Our results will provide critical insight into fundamental mechanisms mediating guided neuronal migration in the developing cerebral cortex, which is imperative for understanding and eventually treating severe disorders of cortical connectivity.
Disruptions to the formation of inhibitory circuitry in the cerebral cortex confer risk for profound brain disorders, including epilepsy, autism, and schizophrenia. Results obtained from the proposed project will provide key information into the mechanisms underlying cortical interneuron migration and maturation-critical processes in assembling functional cortical circuitry. This fundamental knowledge is a pivotal step towards unraveling complex etiologies of neurologic and neuropsychiatric disorders.
