The idea of repairing damaged neuronal circuitry in the mammalian central nervous system (CNS) has challenged neuroscientists for centuries. This is mainly due to the notorious inability of neurons to regenerate and the unparalleled cellular diversity of the nervous system. In the mammalian cerebral cortex, one of the most complex areas of the CNS, multipotent neural stem and progenitor cells undergo progressive specification during development to generate the staggering variety of projection neuron subtypes that are found in the adult. How is this process orchestrated in the embryo? And, can developmental signals be used to regenerate projection neuron subtypes in the adult or in the dish? Here, we first provide an overview of the diversity and fate potential of neural progenitors of the cerebral cortex during development. Further, we discuss the plasticity of neural progenitors and the roles of intrinsic and extrinsic signals over progenitor fate. Finally, we discuss the relevance of developmental signals for efforts to direct the differentiation of pluripotent stem cells into specific types of cortical projection neurons for therapeutic benefit.
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