Cortical development: View from neurological mutants two decades later

Two decades ago we reviewed contributions of investigations based on neurological mutant mice to our understanding of the development of cortical structures of the central nervous system (Caviness and Rakic, 1978). At the time, there was an air of optimism that such mutations, occurring at a single genetic locus, might enable a"genetic dissection" of molecular mechanisms of regulation of brain development. It was even imagined that spontaneous mutations in inbred strains of mice might match as analytic tools in developmental neurobioiogy the modified or selected genes in Drosophila. For students of cortical development, the autosomal recessive reeler mutation, mapped to chromosome 5 in mice (Falconer, 1951; Caviness and Sidman, 1972), was particularly promising for several reasons. First, it was associated with systematic patterns of neuronal malposition in virtually all cortical structures. Second, the abnormal patterns of neuronal position were essentially invariant despite variations in genetic background and in the mutation itself (Caviness et al., 1972; see later Wilson et al., 1981). Third, the abnormal pattern appeared to be unassociated with death or degeneration of cortical neuron classes. Rather, it seemed to reflect an error in the specific molecular mechanisms through which cellular interactions govern pattern formation in the course of cortical histogenesis. The quest to elucidate the nature and mechanisms of such cellular interactions was then, and has remained, a central motivation in developmental neurobiology. In the intervening years, the high expectations inspired by reeler and other mutations in mice affecting development of the central nervous system have not been realized. Whereas research with mutations in invertebrates, such as fruitflies and nematodes, has penetrated ever more deeply into mechanisms of molecular regulation of histogenesis, the yield from neurological mutant mice has been feeble. Both authors of the present review, among many other investigators, eventually abandoned work with mutant mice as a research strategy in developmental neurobiology. Now, nearly 20 years later, a set of three publications in recent issues of Nature, Nature Genetics, and Neuron signal a decisive assault upon the reelergene and promise to "jump start" investigations into the developmental neurobiological role of its encoded protein. The achievements of these teams of investigators are substantial. The illusive reeler gene located on chromosome 5 has been decoded. This has led to inferences about the developmentally active properties of the encoded protein, and the spatial and temporal patterns of expression of the gene transcript have been mapped in the normal developing animal (D'Arcangelo et al., 1995; Hirotsune at al., 1995). Furthermore, the spatial and temporal patterns of distribution of a polypeptide that is a plausible candidate for the product of the reeler gene have also been mapped in the normal embryo. Preliminary studies suggest that antibodies against this protein induce in vitro a class of anomalous cell reaggregation patterns akin to that occurring in developing cortical structures of the mutant (Ogawa et al., 1995).