Three-dimensional models of human brain development

Abstract The makeup and distribution of cell-to-extracellular matrix and cell-to-cell interactions, in their dynamic unfolding, ground the development and maintenance of tissues and organs. The function of the brain, due to its unparalleled complexity, is exquisitely dependent on its tissue architecture for proper development and performance, though these are also eminently plastic in their range of adaptive and/or compensatory potential. Indeed, the fine-tuning between resilience and plasticity through the development and maintenance of brain structure and function has long been a core theme within neuroscience and stem cell biology, yet its human-specific features have evaded experimental tractability until recently. This has now changed with the rise of three-dimensional (3D) cultures, which, while not an absolute novelty per se, have massively accelerated their reach into both foundational and applied research contexts. This is largely due to the advent of reliable renewable sources of human pluripotent cells and the expanding repertoire of protocols that mimic in vivo developmental processes with higher accuracy. In this chapter we set out to frame the most salient aspects of human brain development, with special emphasis on the neocortex, in terms of the key aspects of experimental models based on genetic reprogramming that recapitulate human cortical architecture, focusing on the properties emerging from this level of tissue organization and their role in uncovering the genetic and epigenetic mechanisms governing brain development.