Genetic Control of Cortical Development

Abstract

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 regulatory 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 reflect 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 flies 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 flies 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