The Reeler Mouse: Anatomy of a Mutant

Reeler is a well-characterized autosomal mutation in the mouse that affects several aspects of brain development. The first known reeler mutation occurred spontaneously in 1948, in an inbred mouse colony in Edinburgh, Scotland, and was thus referred to as rl^Ed. Mutant mice, which appeared in this strain at the frequency expected for a recessive trait according to classical Mendelian inheritance, were severely ataxic and exhibited a characteristic reeling gait that conferred them their name. Anatomical studies indicated that all major cortical structures of the brain were present, but appeared disorganized in reeler mutants. Strikingly, projection neurons were shown to connect properly to their ectopic targets. For example, thalamocortical projections terminated properly on neurons destined for cortical layer IV, even though these occupied abnormal positions in the reeler cortex (Molnar et al., 1998; Steindler and Colwell, 1976). Climbing fibers also terminate properly on ectopically positioned Purkinje cells in the reeler cerebellum, although subtle defects in the number and position of their synaptic boutons are present (Mariani, 1982). The observation that all major neuronal types are born at the correct time in the reeler brain, but end up in the wrong location led to the realization that the study of the reeler mouse could provide exquisite insights into the mechanisms of neuronal migration and cortical layer formation (reviewed by Caviness and Rakic, 1978; D'Arcangelo and Curran, 1998; Goffinet, 1984b; Lambert de Rouvroit and Goffinet, 1998). Indeed, an entirely novel signaling pathway was discovered following the identification in 1995 of the reeler gene, which was called reelin (D'Arcangelo et al., 1995). This gene is mutated not only in the original rl^Ed strain, now designated Reln^rl and commercially available from The Jackson Laboratory, but also in several other reeler mouse strains. All of the known reeler strains lack functional Reelin protein and are therefore null (Andersen et al., 2002; D'Arcangelo and Curran, 1998). Most strains lack reelin mRNA expression altogether, due to large deletions of the gene or exon skipping that renders the transcript highly unstable. The Orleans strain (rl^Orl) is unique in that a small 3' deletion in the coding sequence, due to a retroviral insertion, gives origin to a Reelin protein that lacks the C terminus and cannot be secreted (D'Arcangelo et al., 1997; de Bergeyck et al., 1997). The phenotype among all reeler strains is essentially the same. Recently, two reelin-deficient rat strains have been described (Kikkawa et al., 2003; Yokoi et al., 2003). The Shaking Rat Kawasaki (SRK) and the Komeda Zucker Creeping (KZC) rats display all of the typical anatomical features of the mouse reeler mutation. These animals may be of particular use for future behavioral and pharmacological studies, for which the rat is the preferred species. This chapter will describe the most salient anatomical aspects of the reeler mutation, I will then recapitulate the key molecular discoveries and finally attempt to integrate these findings into a framework that explains how Reelin may regulate brain development and function.