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Genetic Control of Cortical Development John L.R. Rubenstein and Pasko Rakic1 Nina Ireland Laboratory of Developmental Neurobiology, Center for Neurobiology and Psychiatry, Department of Psychiatry and Programs in Neuroscience, Developmental Biology and Biomedical Sciences, 401 Parnassus Avenue, University of California at San Francisco, CA 94143-0984 and 1 Section on Neurobiology, Yale University School of Medicine, SHM, C-319, 333 Cedar Street, New Haven, CT 06510, USA The cerebral cortex is the highest achievement of biological evolution and the neural substrate of human mental abilities. Molecular biological techniques have opened the possibility of investigating how specific regulator y genes and morphoregulatory molecules mediate formation of this complex structure. During evolution, the cerebral cortex has undergone disproportionate growth relative to the rest of the brain [reviewed by Northcutt and Kaas (Northcutt and Kaas, 1995)]. This increase predominately affected its surface area, rather than its thickness, and was accompanied by the addition and elaboration of functional subdivisions. Furthermore, the [deletion] region that has increased in size the most, the neocortex, acquired a characteristic laminar structure that is not readily apparent in the cortex of non-mammalian vertebrates. These changes in the size, complexity and histological organization of the cerebral cortex presumably ref lect the elaboration of the cortical circuitry which ultimately endowed the human brain with its extraordinary capacity for reasoning and language. The cortex, or pallium, is comprised of several subdivisions. In mammals, these functionally distinct regions include the hippocampus, parahippocampal areas, neocortex, entorhinal cortex, olfactory cortex, claustrum and olfactory bulb. Each has characteristic histological features, wiring diagrams and functionally distinct subdomains. Based on cytoarchitectonic criteria, the human cerebral cortex was subdivided into more than 50 areas (Brodmann, 1909). More recent methods are revealing even greater complexity in the categories, number and functional significance of cortical parcellation (Felleman and Van Essen, 1991). The remarkable conservation of the pattern of areal divisions within a given species suggests the existence of a highly conserved and rigidly regulated regional specification program that controls their development (Rakic, 1988). The evidence presented in this issue of Cerebral Cortex is in accord with the view that neocortical regional specification depends on interactions between intrinsic properties of cortical cells with input from subcortical structures. Cortical development has been scrutinized by developmental neurobiologists during this century. Their studies provide an essential physiological, anatomical and cellular foundation for elucidating the molecular mechanisms that regulate its assembly. The discovery of genes that regulate brain development is now revolutionizing our ability to understand the intricacies of neuroembryology, and to identify how neuropathological processes derail cortical development. Genetic studies of invertebrate development in f lies and nematodes have had a fundamental role in expediting the progress. The identification of genes that regulate regional specification (e.g. gap and homeotic genes), segmentation (e.g. segment polarity genes), neurogenesis (e.g. neurogenic and proneural genes) and programmed cell death (apoptotic genes) provided key insights into regulatory genes that could control early development of the vertebrate brain. In the mid-1980s, the first mammalian homologs of genes that control early development in Drosophila were identified; these included the Hox genes. The expression of these genes have distinctive anteroposterior boundaries in the vertebrate spinal cord and hindbrain. Their expression patterns provided new evidence for a neuromeric, or segmental organization of the hindbrain [reviewed by McGinnis and Krumlauf (McGinnis and Krumlauf, 1992)]. Vertebrate homologs of Drosophila segment polarity genes, such as engrailed and wingless, have been found to be expressed in the midbrain and hindbrain [reviewed by Joyner (Joyner, 1996)]. By the late 1980s, the first candidates for genetic regulators of forebrain development began to be reported. These are the Brn genes, which were identified by their homology to the POU family of transcription factors that regulate mammalian pituitary development, and other developmental processes in f lies and worms [reviewed by Wegner et al. (Wegner et al., 1993)]. The Brn genes are expressed in the forebrain and in other regions of the central nervous system (CNS). In 1990, a mouse homolog of the Drosophila neurogenic basic helix–loop– helix transcription factor achaete-scute (Mash1) was reported; like the Brn genes, Mash1 is expressed in the forebrain, as well as in more posterior regions of the CNS (Lo et al., 1991). Then, in 1991, the first forebrain-specific regulatory genes were reported: Dlx1, Dlx2 and Nkx2.1 (TTF1; T/ebp) [reviewed by Rubenstein and Puelles (Rubenstein and Puelles, 1994)]. These homeobox genes were identified either through a directed search for forebrain regulatory genes, or by their homology to other homeobox genes, or by serendipity. Within a year, the Otx and Emx genes, homologs of the orthodenticle and empty spiracle genes that control Drosophila head development, were found to be expressed in nested patterns in the mouse forebrain and midbrain [reviewed by Boncinelli et al. (Boncinelli et al., 1993)]. By 1993, vertebrate homologs of Drosophila genes encoding secreted morphogens and patterning molecules, such as hedgehog and decapentaplegic, were demonstrated to be expressed in longitudinal stripes along the ventral and dorsal aspects of the entire neuraxis [reviewed by Tanabe and Jessell (Tanabe and Jessell, 1996) and Shimamura and Rubenstein (Shimamura and Rubenstein, 1997)]. Finally, several genes that regulate the number and survival of cells in the nematode, through regulating apoptosis (Metzstein et al., 1998), were found to play a similar role in the mammalian forebrain (e.g. caspase-3 and -9) (Kuida et al., 1996, 1998). The regional distribution of apoptotic cells in the mouse CNS appears to be regulated by the combination of Jnk1 and Jnk2 kinases (Kuan et al., 1999), genes that were also identified in Drosophila [reviewed by Haydar et al. (Haydar et al., 1999)]. The expression patterns of these regulatory genes frequently exhibit discrete anteroposterior (transverse) and dorsoventral © Oxford University Press 1999 Cerebral Cortex Sep 1999;9:521–523; 1047–3211/99/$4.00 (longitudinal) boundaries, which suggested a Cartesian-like organization for parts of the forebrain. These findings led to the Prosomeric Model, which suggests that the diencephalon, and perhaps more rostral forebrain regions, have a segment-like organization similar to that of the hindbrain (Puelles and Rubenstein, 1993; Rubenstein et al., 1994). In parallel with the discoveries of genes that control brain patterning and differentiation, genes were identified which encoded secreted and cell-surface proteins that regulate cell–cell interactions, axon path-finding and cell migration. The advent of targeted mutagenesis in mouse has made it possible to discover the functions of these genes, and in most cases has confirmed their essential roles in controlling brain development. The papers in this Special Issue of the Cerebral Cortex focus on genes that are implicated in controlling regionalization, morphogenesis and differentiation of the cerebral cortex, processes which undoubtedly control cortical size, cell-type specification and connectivity. The papers review recent advances in molecular genetics that have illuminated mechanisms of cortical development beginning from its earliest stages through early postnatal life. The chapters by Acampora et al. (Acampora et al., 1999), Arimatsu et al. (Arimatsu et al., 1999), Dou et al. (Dou et al., 1999), Eagleson and Levitt (Eagleson and Levitt, 1999), Rubenstein et al. (Rubenstein et al., 1999), and Grove and Tole (Grove and Tole, 1999) review possible mechanisms for induction and regionalization of the cortex. Rubenstein et al. describe patterning centers in the neural plate and prosencephalon which produce potential morphogens, and some of the transcription factors that interpret these patterning signals (Rubenstein et al., 1999). Acampora et al. focus on the early roles of the Otx homeobox transcription factors in patterning the midbrain and forebrain, and their later roles in cortex differentiation (Acampora et al., 1999). Dou et al. describe the role of BF1, which encodes a winged-helix transcription factor that is required for telencephalic patterning and proliferation (Dou et al. 1999). Arimatsu et al. and Eagleson and Levitt review studies that have used the latexin, lamp and other genes to study the process of regional specification of the lateral cortex (Arimatsu et al., 1999; Eagleson and Levitt, 1999). Grove and Tole consider mechanisms that control patterning of the medial cortex, the region that gives rise to the hippocampus (Grove and Tole, 1999). Several of the papers describe genes whose expression defines regional boundaries in the developing cerebral cortex. These genes are useful markers in experiments aimed at elucidating the mechanisms that generate cortical subdivisions. For instance, in the paper by Rubenstein et al. evidence is presented that expression of the Id2 gene respects the boundary of the sensory and motor neocortex (Rubenstein et al., 1999). Papers by Hatanaka and Jones, and Grove and Tole describe several genes that are regionally expressed in medial aspects of the cortex, particularly in the region of the hippocampus (Hatanaka and Jones, 1999; Grove and Tole, 1999). Papers by Donoghue and Rakic, Mackarehtschian et al. and Rubenstein et al. describe the regional expression of Eph receptor tyrosine kinases and their ligands (ephrins) in the cerebral cortex (Donoghue and Rakic, 1999; Mackarehtschian et al., 1999; Rubenstein et al., 1999). These genes, some of which are expressed in gradients, and others in discrete domains, are likely candidates for regulating topographic maps and distribution of inputs to the cortex as has been suggested in subcortical structures (O’Leary and Wilinson, 1999). The papers by Gitton et al. and Rubenstein et al. discuss the roles of thalamic afferents in regulating regionalization of the 522 Genetic Control of Cortical Development • Rubenstein and Rakic neocortex, and review the evidence that a considerable degree of regionalization of the cerebral cortex occurs before the arrival of thalamic afferents, as predicted by the existence of an intrinsic protomap within the cerebral vesicle (Gitton et al., 1999a; Rubenstein et al., 1999) [see also Rakic (Rakic, 1988)]. Gitton et al.’s study suggests that some neocortical regions are specified at ver y early stages of telencephalon development although this prepattern is revealed only once thalamic afferents grow into the neocortex (Gitton et al., 1999a) [see also Gitton et al. (Gitton et al. 1999b)]. Finally, Rubenstein et al. (Rubenstein et al., 1999) refer to recent experiments demonstrating a remarkable degree of neocortical regionalization in the absence of thalamic inputs (Miyashita-Lin et al., 1999). Evolution of the cortex has been postulated to occur in part through changes in the proliferation of neuronal precursors in the ventricular zone and allocation of postmitotic cells to their proper laminar and areal positions in the cortical plate (Caviness, 1995; Rakic, 1995). Papers by Dou et al. and Warren et al. discuss the roles of the BF1 and Pax6 genes, respectively, in regulating proliferation in the developing cortex (Dou et al., 1999; Warren et al., 1999). The number of cortical neuronal and glial cells also depends also on programmed cell death (PCD or apoptosis) that occur in the germinal layers prior to onset of neurogenesis. Targeted disruption of cell death-effector genes such as caspase-3 and caspase-9 and Jnk1/2 revealed that cells must die on schedule and in the proper position in the proliferative zones. Knockout mice lacking both copies of these genes have an increased number of founder cells in the ventricular zone that eventually generate supernumerary cortical neurons resulting in an expanded cerebral surface that shows sign of convolutions (Haydar et al., 1999). The control of cell-type identity within the cortex is the subject of the paper by Anderson et al. (Anderson et al., 1999). Of the two major classes of neurons in the cortex — projection neurons, which are glutaminergic, and interneurons, which are mainly GABAergic — several studies now indicate that many of the latter are produced in the basal ganglia, rather than derived from the proliferative zone of the neocortex. While GABAergic neurons originating from the basal ganglia migrate tangentially into the cerebral cortex, most projection neurons originating in the ventricular zone migrate radially (Ware et al., 1999). GABAergic neurons appear to originate from at least two distinct sources and migrate along at least two distinct pathways. Furthermore, the genetic control of interneuron and projection neuron development appears to be distinct, as the Dlx genes regulate the former and genes such as Pax6, Otx1 and Tbr1 regulate the latter. New evidence is presented which suggests that Dlx genes can in fact induce the GABAergic phenotype (Anderson et al., 1999). Thus radial and tangential cell migration seem to be used by distinct cell types in cortical development. The modes of migration and genes that regulate their allocation to the cortex are discussed by Ware et al. (Ware et al., 1999). Advances in this area are beginning to provide insights into the etiologies of neuronal migration disorders in humans (Walsh, 1999). Finally, inroads into the mechanisms controlling axon pathfinding are illuminating how cortical connections are formed. Discussion of some aspects of this subject is presented in the chapters by Arimatsu et al., Hatanaka and Jones, and Rubenstein et al. (Arimatsu et al., 1999; Hatanaka and Jones, 1999; Rubenstein et al., 1999). A number of mouse mutants are yielding new insights into the molecules and mechanisms that connect cortical cells to cortical and subcortical targets. Thus, in spite of the differences in functional requirements, cortical representation of the somato- sensory and visual systems can be established independently of cues by synaptic activity, as has been found in the olfactory system (Bulfone et al., 1998; O’Leary et al. 1999). In conclusion, rapid progress is being made in the identification of the genes controlling cortical development. The stage is now set to describe in detail the genetic programs that regulate the processes that control regional specification, morphogenesis, cell type specification, neuronal migration and connectivity. Inroads have been made in identifying genes that control the size of the cerebral cortex through regulation of proliferation and cell death. Regionalization of the cortex appears to be controlled by patterning centers that control the activation of transcription factors that determine areal fate and the expression of cell surface molecules that control the topographic organization of synaptic inputs and outputs. Specific cell types appear to be generated in distinct locations within the telencephalon. Tangential migration introduces interneurons that are generated in the basal ganglia but destined to migrate to the cerebral cortex. On the other hand, radial migration pathways are used to generate the characteristic laminar structure of the mammalian cerebral cortex and are probably essential for maintaining the positional information of projection neurons that is required for correct connectivity. Finally, while inputs from the thalamus appear to have little inf luence on early regionalization of the cortex, they are necessary for controlling its maturation. It is likely that understanding these fundamental processes will shed light on the similarities and differences of cortical structure in distinct vertebrate species and the mechanisms that have constrained evolutionary change. We also expect that this information will help in the search for methods to diagnose and treat human neuropsychiatric and neurological disorders. Finally, we hope that this Special Issue of Cerebral Cortex will provide a useful resource to scientists interested in this subject, and that it will stimulate new ideas and experimental approaches. References Acampora D, Barone P, Simeone A (1999) Otx genes in corticogenesis and brain development. Cereb Cortex 9:533–542. Anderson S, Mione M, Yun K, Rubenstein JLR (1999) Differential origins of neocortical projection and local circuit neurons: role of Dlx genes in neocortical interneuronogenesis. Cereb Cortex 9:646–654. 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