The most innovative aspect of this proposal lied 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 offered an unparalleled solution and permitted quantitative clonal analysis, concurrent with genetic manipulation, of precise division patterns and lineage progression at unprecedented individual progenitor cell resolution. The completed research along the LinPro project led to significant new insights, and provided an inaugural but definitive quantitative mechanistic understanding of neural stem cell lineage progression and cortical development at single cell resolution. Our findings are currently being translated to other brain regions and new research projects will determine the generality of our findings. In a broader context, our findings along LinPro also provide deeper understanding of brain function and why human brain development is so sensitive to disruption of particular signaling pathways in pathological neurodevelopmental disorders. Our obtained results also contributed to our knowledge of cortical neuron and/or glia specification and thus provide a basic foundation for prospective embryonic stem cell-based approaches in the context of directed brain repair.
