The search for truth is in one way hard and in another way easy, for it is evident that no one can master it fully nor miss it wholly. But each adds a little to our knowledge of nature, and from all the facts assembled there arises a certain grandeur. (Aristotle, Metaphysics 993a.30–993b.3)
It has been over 30 years since a group of developmental biologists and neuroanatomists met in Boulder, Colorado, to agree on terminology and develop a conceptual framework for what was then known about the early stages of cerebral cortical development. The results were published in a landmark paper bearing the simple imprimatur of the ‘Boulder Committee Report’. It is difficult to imagine that a cutting-edge assessment of any area of neurobiology could stand unchallenged for a few years, let alone decades, but the authors achieved this and more. At a recent international meeting held at Delphi, Greece, the current state of knowledge concerning cortical development was discussed intensively, and many of the contributions presented there form the basis for this issue of Cerebral Cortex. The terminology adopted by the Boulder Committee so many years ago was reconsidered by those in attendance, and found to be in most respects still current. Thus, the basic anatomical framework proposed by the Boulder Committee, including the terms used to describe the layers of the developing cortex, are still valid (Fig. 1). This is not to say that there has been no progress in our understanding of cortical development; quite the contrary, there has been a virtual sea change in our concepts of how cortical neurons are generated, where they are born, and how they migrate. In fact, our understanding of the basic developmental processes of neuronal induction, regionalization, neurogenesis and migration have undergone dramatic alterations within the last decade. The contributions presented in this issue touch upon many of these developments and may serve as an introduction to current concepts of cortical development. The developmental mechanisms described here begin to address the question of ‘how’, and may complement the structural foundation provided by the Boulder Committee that established a consensus view of ‘what’ and ‘where’.
How the cerebral cortex becomes parceled into areas, each with distinct morphological and functional traits, is one of the most fundamental questions in neuroscience. How do these distinct cortical areas acquire their identity during development? Two alternative hypotheses have been hotly debated since the late 1980s: the ‘protomap’ concept, suggesting that molecular cues intrinsic to the proliferative zone determine cortical identity, and the ‘protocortex’ model, which proposes extracortical influences on cortical regional identity. Recent evidence, however, favors the middle ground. Thus, it is now accepted that whereas late refinement of area differentiation relies on structural and functional integrity of thalamic afferents, the early cortical primordium has the intrinsic capability to undergo molecular regionalization presaging the later development of mature areal properties. Much work in recent years has focused on the role of transcription factor genes in early cortical arealization. Researchers have used mouse mutants to show that parcellation of cortical areas is regulated by gradients of homeodomain proteins, but the mechanisms that underlie these complex processes are presently under intensive investigation. Work has only recently begun to shed light on the role of diffusible ligands in establishing transcription factor gradients responsible for sculpting cortical areal profiles. The question of cortical arealization will undoubtedly remain in the forefront in the field of cortical development for some years to come.
Merging of Glial and Neuronal Lineages: Neurogenesis by Radial Glial Cells
Since the time of the Boulder Committee meeting, a major advance has been in the methods that allow analysis of cell lineages both in vivo and in vitro. One of the intriguing new concepts discussed herein relates to the role of radial glial cells. Glial and neuronal lineages had been thought to be distinct, but results from a number of laboratories now indicate that these lineages are not as divergent as previously thought, and that radial glial cells are indeed neuronal precursor cells. Thus, in addition to their role in guiding migrating neurons, radial glia are now known to be neurogenic and have been shown to give rise to the pyramidal neurons of the cerebral cortex. Moreover, in the few niches where there is persistent neurogenesis in the adult forebrain, it appears that astroglial cells, lineally related to embryonic radial glia, function as neuronal precursor cells. It can be argued that if glial cells are by definition ‘non-neuronal’, perhaps radial glia should be renamed. An appreciation of the broadened role of the radial glial cell in brain development leaves many important questions unanswered. Among these are how prevalent neurogenic radial glia are in brain and cortical development, whether there is heterogeneity of precursor potential among cortical radial glia, and what molecular features distinguish them from their neuroepithelial cell precursors and the astrocytes into which they transform.
Inhibitory Interneurons Arise from the Ventral Telencephalon
Given the segmental origin of the neuroaxis and the restriction of regionally expressed gene products at anatomical boundaries, it was a reasonable assumption that neurons destined for a particular segment would arise within that segment during development. The demonstration that significant numbers of neurons destined for the neocortex actually arise in the striatal anlage came as a surprise to many. More remarkable still, the cortical cells originating in the ventral telencephalon seem to consist entirely of inhibitory interneurons, while the excitatory principle neurons arise from the dorsal telencephalon. These cell types take markedly different routes of migration to converge in the developing neocortex and join together synaptically to form the canonical cortical circuit, where excitation is accompanied by feed-forward and feedback inhibition. Understanding the underlying molecular and cellular mechanisms that regulate regional neurogenesis and direct the migration of immature neurons poses a daunting challenge. Nonetheless, significant inroads have been made recently through the application of molecular biological and genetic tools. Some of these exciting new insights into the genetic control of neurogenesis and migration are presented here.
Multiple Modes of Neuronal Migration
Around the time of the Boulder Committee Report, the migration of cortical neurons along radial glial fibers had been recently described. It was subsequently widely assumed that glial-guided neuronal migration was the predominant method by which neurons were dispersed in the developing nervous system, despite a minority view that alternative modes of migration were also important. However, the traditional view of radial migration has recently been altered by convincing demonstrations that large numbers of cortical neurons migrate tangentially rather than radially, and that some radially migrating neurons do not appear to climb along radial glial fibers. The inhibitory interneurons that migrate to the developing cortex from the ventral telencephalon, for example, migrate tangentially, crossing generally at right angles to the predominant direction of radial glial fibers. Moreover, a subset of cells arising in the cortical ventricular zone may inherit the radial fiber of parent radial glial cells and migrate by somal translocation along their own radial fibers. These observations are producing a broader and more detailed view of cortical development, but one that will surely undergo further modification in time.