The most innovative aspect of this proposal lies in its interdisciplinary approach to address a fundamental question in neuroscience: What are the cellular and molecular mechanisms in cortical stem cell progenitors regulating the balance between proliferation and differentiation into neurons and/or glia cells, to specify the cerebral cortex of the correct size and cellular composition? While previous efforts greatly contributed to our current framework of neocortical genesis, experimental paradigms were mostly based upon whole population approaches (e.g. full and/or conditional knockout studies). However, the lack of true single cell resolution of progeny fate vital for dissecting progenitor division patterns has previously precluded a definitive understanding. MADM offers an unparalleled solution and permits quantitative clonal analysis, concurrent with genetic manipulation, of precise division patterns and lineage progression at unprecedented individual progenitor cell resolution. The future research along the LinPro project promises significant new insights, and shall provide a definitive quantitative mechanistic understanding of neural stem cell lineage progression and cortical development at single cell resolution. Our findings may potentially also be translated to other brain regions. Ultimately, such advances can result in a deeper understanding of brain function and why human brain development is so sensitive to disruption of particular signalling pathways in pathological neurodevelopmental or psychiatric disorders. In a broader context, the anticipated results likely also contribute to our knowledge of cortical neuron and/or glia specification, and may reveal a logic that can generate cellular diversity; thus providing a possible foundation for prospective future embryonic stem cell-based approaches in the context of directed brain repair.