The cerebral cortex, the seat of our cognitive abilities, is composed of an intricate network of interconnected neurons. The cortical cytoarchitecture consists of distinct layers with different cellular composition and function. Due to an immense heterogeneity in the cortical neuron types it is currently not known how many classes and which subtypes of cortical neurons make up the distinct cortical microcircuits in different functional cortical areas. The precise mechanisms of how these neurons coalesce into defined laminae and form specific connections with their synaptic partners during development are not well understood either. In a pursuit to obtain in-depth insights into these fundamental questions, we assess corticogenesis at unprecedented single cell resolution using the unique genetic strategy called MADM (Mosaic Analysis with Double Markers). MADM technology offers an unparalleled approach to visualize and concomitantly manipulate sparse clones and small subsets of genetically defined neurons in mice. Within the scope of this project we will use multidisciplinary experimental approaches including but not restricted to mouse genetic techniques and MADM, high resolution 4D live-imaging, and gene expression profiling. It is our objective to establish a research program with the following major aims: 1) Determination of cortical neuron lineages by clonal analysis; 2) Dissection of the molecular mechanisms of cortical neuron migration and 3) Probing of genomic imprinting, an epigenetic phenomenon, in cortex development. Together, these research directions shall precipitate into significant conceptual progress regarding the fundamental cellular, molecular and epigenetic principles of cerebral cortex development. Ultimately, such advances may result in a deeper understanding of brain function and of why human brain development is so sensitive to the disruption of particular signaling pathways in pathological neurodevelopmental or psychiatric disorders.
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