Preface

The evolution of mammalian brains, notably that of the human brain, has fascinated researchers for a long time. Inseparably linked to this evolution is the process of the development of mammalian brains. In this context, a mammalian-specific part of the brain that is of particular interest is the neocortex, the phylogenetically youngest part of the cerebral cortex. The neocortex is the seat of: sensory perception, generation of motor commands, and higher-order brain functions such as cognition and - in humans - language. An essential foundation underlying neocortex function is neurogenesis, a complex process in which the generation of neurons from cortical stem and progenitor cells (cSPCs) has a central role, but which also comprises subsequent steps such as the migration of new-born neurons to the appropriate neuronal layer of the six-layered neocortex. Topics inherent in or related to neocortical neurogenesis include (i) cell lineages within the various cSPCs and from cSPCs to neurons, (ii) the generation of diverse types of neurons, (iii) the specification of cortical regions, (iv) cortical folding, and (v) cortical malformations. It is precisely these issues that this book addresses.

I am grateful, and indeed feel honored, that of the leading researchers - and in fact pioneers - in the field whom I approached, the overwhelming majority agreed to become contributors to this book. Thanks to the wonderful efforts and major discoveries of these many colleagues and their associates, the 33 chapters of this book together provide a near-comprehensive up-to-date overview of neurogenesis in the developing neocortex and its evolutionary adaptations.

Before describing the various sections and chapters of this book, a brief introduction to the germinal zones, classes and types of cSPCs, and their terminology may be helpful. The wall of the developing neocortex with its various zones and layers arises from the neuroepithelium and retains a fundamental feature of the latter - apical-basal polarity. Thus, the ventricular surface corresponds to the apical side of the developing cortical wall, and the pial surface to its basal side. There are two principal germinal zones. First, the ventricular zone (VZ); it is the primary germinal zone, is the apical-most zone of the developing cortical wall, borders the ventricle, and is the zone most closely related to the neuroepithelium. Second, the subventricular zone (SVZ); it is a secondary germinal zone arising from the VZ and is located adjacent to the basal side of the VZ. In many mammalian species, notably those developing a relatively large and folded (gyrencephalic) neocortex such as the human, the SVZ is divided into two subzones, called the inner SVZ (iSVZ), which is located basally to the VZ, and the outer SVZ (oSVZ), which is located basally to the iSVZ. In line with this localization of the germinal zones along the apical-basal axis of the developing cortical wall, the cSPCs whose cell bodies reside in the VZ constitute one cSPC class and are collectively referred to as apical progenitors (APs), and the cSPCs whose cell bodies reside in the SVZ constitute the other cSPC class and are collectively referred to as basal progenitors (BPs). The major types of APs are the neuroepithelial cells, which transform into radial glia and are called either apical or ventricular radial glia; in turn these transform into the truncated radial glia. Additional types of APs are discussed in the respective chapters. The major types of BPs are the basal intermediate progenitors, sometimes simply referred to as intermediate progenitors, and the delaminated radial glia called either basal or outer radial glia.

The first section of the book focuses on cSPCs and the germinal zones in which they reside. Magdalena Götz and Florencia Merino open this section with their chapter describing the discovery and role of radial glial cells as neural stem cells. Arnold Kriegstein and Alex Pollen then review the diversity of cSPCs in the developing human neocortex and discuss how the contribution of progenitor cells to the structure of the neocortex underwent changes in the course of human evolution. This is followed by Robert Hevner's chapter, which focuses on the role of one type of BP, the intermediate progenitors, in the development and evolution of the neocortex. Colette Dehay and Henry Kennedy then concentrate on a germinal zone first described in the developing macaque neocortex, the oSVZ, whose BPs have a key role in shaping the cytoarchitecture, in particular, of the primate neocortex. Víctor Borrell and Virginia Fernández subsequently broaden the evolutionary aspects of the role of cSPCs in neocortex development by comparing the cSPC-based neurogenesis in mammalian brains to the neurogenesis and progenitor cells in the developing brains of reptiles and birds. The following two chapters address two specific features of cSPCs. Ryoichiro Kageyama and Hiromi Shimojo concentrate on the role of basic helix-loop-helix transcription factors in the regulation of the proliferation and differentiation of neuroepithelial cells and radial glial cells. Takaki Miyata discusses biophysical issues, notably the mechanical forces that are relevant for the APs in the VZ, in particular the forces associated with the interkinetic nuclear migration of these cSPCs. Finally, my colleagues Lei Xing, Anneline Pinson, Felipe Mora-Bermúdez, and I discuss the role of human-specific genes and amino-acid substitutions that affect cSPC behavior and thereby influence human neocortex development in crucial ways, with relevance for neocortex expansion and modern human vs. Neanderthal differences in neocortical neurogenesis.

Linked to this discussion of the various classes and types of cSPCs and their key features, the following section of the book addresses, in two chapters, the topic of cell lineages within the various cSPCs and from cSPCs to neurons in the developing neocortex. Fumio Matsuzaki, Quan Wu, Merve Bilgic, and Yuji Tsunekawa first discuss the diversity of APs in the VZ and then report on the heterogeneity of radial glial cell lineages in the developing neocortex of the ferret, a gyrencephalic carnivore. This leads these authors to raise the issue of the temporal scaling of neocortex development, in the context of cSPC diversity, across three frequently studied mammalian species, the lissencephalic mouse, the gyrencephalic ferret and the highly gyrencephalic human. The second chapter in this section by Simon Hippenmeyer, Ana Villalba, and Nicole Amberg concentrates on the topic of radial glial cell lineage progression in the developing neocortex all the way to neurons and, eventually, to glial cells, and discusses cell-autonomous vs. non-cell-autonomous cues that affect this progression. In this context, the authors describe the MADM technology for the study of radial glial cell lineage progression and address specific genes that control this progression.

Following these two sections on cSPCs, the next section of the book addresses the generation of the various types of cortical neurons. Paola Arlotta and Ana Uzquiano open this section by discussing the mechanisms underlying projection neuron diversification and the use of human brain organoids to investigate human-specific features of neuron diversification. Tarik Haydar, Zhen Li, and William Tyler then link the topic of projection neuron diversity to the heterogeneity of cSPCs and discuss human developmental disorders resulting in alterations of cortical neurogenesis that affect neuron diversity. Nenad Sestan and his associates Navjot Kaur, Rothem Kovner, and Kevin T. Gobeske further broaden these discussions not only by addressing the topics of laminar and areal identity of cortical projection neurons, but also by introducing the subjects of human specializations of cortical projection neurons and their circuitry, and of human neuropsychiatric disorders. Denis Jabaudon, Esther Klingler, and Sergi Roig Puiggros then focus on cell-intrinsic and cell-extrinsic mechanisms that are involved in the emergence of cortical areas, and address the topic of input-dependent differentiation of the various types of cortical neurons, including the inhibitory interneurons. A different facet is introduced in the chapter by Jürgen Knoblich and Catarina Martins-Costa, who dissect the evolution and development of the corpus callosum, a key structure for the transfer of information between the brain hemispheres. Finally, Zoltán Molnár, Thomas Henning, and Sara Bandiera close this section of the book by focusing on a subpopulation of subplate neurons that persists through development into adulthood as layer 6b in mouse and interstitial white matter cells in human, and by discussing a transcriptionally based classification of these cells.

Complementing this section, the following section of the book with its two chapters focuses on the migration of the new-born neurons to the appropriate position within the six-layered neocortex. Laurent Nguyen and Mi´riam Javier-Torrent first discuss the modes of cell migration of the excitatory projection neurons and the inhibitory interneurons and dissect the differences between these two classes of cortical neurons that exist in mammals ranging from rodents to primates. The authors then concentrate on impairments of neuron migration that result in prototypic neuronal migration disorders, and discuss molecular mechanisms that regulate neuron migration and whose disturbances underlie these cortical malformations. Orly Reiner and Aditya Kshirsagar focus on LIS1, the first human gene identified and reported to be involved in neuron migration. The authors provide an in-depth analysis of the mechanisms underlying LIS1 function, its regulation, and its role...