Forward Genetic Analysis of Cortical Circuits and Structure

The mammalian neocortex is a vast cell network with thousands of connections and is susceptible to numerous genetic congenital brain anomalies impacting cortical structure and connectivity. This application leverages forward genetics in mice to identify new genes influencing forebrain neurodevelopment with a specific focus on cortical structure, lamination and axonal pathways. The cerebral cortex and the basal ganglia comprise the two major telencephalic brain regions controlling voluntary movement and intellectual capacities. Our rationale is that by taking an unbiased, forward genetic approach we will uncover new and fundamental discoveries in the genetics of development and neural circuit formation in these two telencephalic brain regions. The major outcome of this proposed research is gene discovery to study both typical neurodevelopment and neuropathology. We will find novel genes which control the formation of forebrain structure and circuits through the use of ENU mutagenesis in mice carrying genetically encoded reporters expressed at early stages of neural development, a novel application of these existing genetic tools to a basic neuroscience question. By completing these studies, we will be positioned to use this information together with the newly developed tools to develop novel hypotheses concerning the etiological mechanisms of mammalian forebrain development and neural circuit formation. We will accomplish the goals of this application by pursuing the following two specific aims: 1) Identify novel genes responsible for proper gross cortical development, lamination, and layer-specific axonal trajectories and 2) Identify novel genes responsible for proper development of the internal capsule and the corticospinal tract. The aims are accomplished through an ENU mutagenesis approach in the mouse. The mutations are then cloned and validated through a number of functional studies. These studies will identify several genes essential for mammalian forebrain structure and function and thus linking genetics to neural phenotypes. The significance of this work is found in the specific application to cortical structure and circuitry, and that an unbiased approach such as this has the capability to implicate entirely new pathways in neurological disease. Such knowledge is not only critical to further understand the basic mechanisms of neurodevelopment, but also has immediate clinical relevance through identification of a number of potential therapeutic targets. Furthermore, these mouse models are novel genetic tools which provide a reusable resource to directly characterize the role of the mutated gene in neurodevelopment, and potentially serve as a tool to test future therapeutic interventions. Taken together, these findings are therefore applicable to basic developmental neurobiology, pediatric and adult neurology, human genetics and genetic counseling.