*Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, OX1 3PT, UK. || Department of Morphology, Institute of Experimental Medicine, St Petersburg, 197376, Russia. § Department of Neurobiology and Kavli Institute of Neuroscience, Yale University Medical School, New Haven, Connecticut 208001, USA. Correspondence to P.R. & I.B. e-mails: pasko.rakic@yale.edu; irina. bystron@dpag.ox.ac.uk doi:10.1038/nrn2252 Neocortex The evolutionarily newest portion of the cerebral cortex. It is particularly enlarged in primates and underpins higher mental functions for humans. Neuroepithelium A layer of proliferating neuroepithelial cells that makes up the neural plate and neural tube. Development of the human cerebral cortex: Boulder Committee revisited Irina Bystron* || , Colin Blakemore* and Pasko Rakic § Abstract | In 1970 the Boulder Committee described the basic principles of the development of the CNS, derived from observations on the human embryonic cerebrum. Since then, numerous studies have significantly advanced our knowledge of the timing, sequence and complexity of developmental events, and revealed important inter-species differences. We review current data on the development of the human cerebral cortex and update the classical model of how the structure that makes us human is formed. The mammalian cerebral cortex is a complex laminated structure that contains a bewildering diversity of neurons and has rich local and extrinsic connectivity. Regional variations in cytoarchitecture are superimposed on a common plan of layers, cell types and connections 1 . The explosion in the size of the cerebral hemispheres during mammalian evolution is correlated with increas- ing behavioural and cognitive capacity. The enormous human cortex underpins our perception, memories, thoughts and language. In all mammals, the neocortex forms at the outer surface of the embryonic cerebral vesicle, at the rostral end of the neural tube, through the migration of neurons from pro- liferative regions near the cerebral ventricle 2,3 . The arrival of migrating neurons establishes laminar compartments, some of which change or even disappear during develop- ment. The sequence of events that take place during corti- cal development, as it was then understood, was described more than 35 years ago by the Boulder Committee 4 . This committee, meeting in Boulder, Colorado, was con- vened by the American Association of Anatomists, the main forum for the growing fields of neuroanatomy and embryology. The committee’s remit was to standardize the heterogeneous and confusing nomenclature for the developing vertebrate CNS that had emerged from the blossoming of knowledge. Richard Sidman presented diagrams of embryonic cortical development (FIG. 1A), based on the observations of P.R., then an assistant professor in his department. The committee’s report stated: The layers and cells of the early developing central nervous system lack direct counterparts in the adult and must be designated by a special terminology. The inconsistent and inaccurate language now in use leads to misunderstanding and a revision is proposed in which the four fundamental zones are termed the ventricular, subventricular, intermediate, and marginal zones. Each is defined according to the form, behaviour, and fate of its constituent cells. All neurons and macroglia of the central nervous system can be derived from these developmental zones. Thus, the committee recommended names for each of the transient embryonic cellular compartments (or ‘zones’) and gave their interpretation of the major devel- opmental events. This model has been widely adopted as a generic description of the development of the entire vertebrate CNS. In the past three decades, experimental studies on normal and genetically altered rodents have driven the analysis of cortical development. This has given us new insights into the regulation of cell division and pro- grammed cell death, which determine neuron number 5,6 , and the mechanisms of neuronal migration 3,7,8 . Patterns of genetic expression are being elucidated, including the expression of transcription factors that are thought to influence regional differentiation and regulate broad aspects of mitotic activity, fate determination and dif- ferentiation 9–12 . Recent studies have revealed new types of transient neurons and proliferative cells outside the classical neuroepithelium, new routes of cellular migration and additional cellular compartments 13–18 . Furthermore, we know much more about intrinsic connectivity and the formation of axonal projections into and out of the cortex 19–21 . Thus, our understanding of the timing and sequence of developmental events in the cerebral wall has changed radically since the work of the Boulder Committee. Despite the march of knowledge, the Boulder Committee’s nomenclature continues to be widely used. Their summary diagram (FIG. 1A) has been reproduced, REVIEWS 110 | FEBRUARY 2008 | VOLUME 9 www.nature.com/reviews/neuro © 2008 Nature Publishing Group