Mutant mice with scrambled brains: understanding the signaling pathways that control cell positioning in the CNS.

Abstract

The characterization of mouse neurological mutants has proven to be an extremely valuable approach to the analysis of central nervous system development (CNS). In particular, over the past four years, remarkable progress has been made toward the identification and characterization of genes that are required for correct cell positioning in the developing brains of mice and humans (D’Arcangelo and Curran 1998; Walsh 1999). This work has provided an impressive collection of genes (Table 1) that play key roles in both the radial and tangential migration of neurons (Pearlman et al. 1998; Hatten 1999). The classical ataxic mutant mouse reeler has served for many years as a prototype for the investigation of neurological mutations affecting neuronal migration and the organization of the CNS. The hallmark of this mutant is the disruption of neuronal cytoarchitecture in the cerebral cortex, cerebellum, and hippocampus (Caviness 1977; Rakic and Caviness 1995). The molecular basis of the reeler phenotype was uncovered by the fortuitous insertion of a fos transgene into the reeler locus, which led directly to the identification of the reelin (Reln) gene (D’Arcangelo et al. 1995). In short succession, the disabled-1 (Dab1) gene was found to be responsible for a reeler-like phenotype in both man-made and naturally occurring mouse mutants (Howell et al. 1997b; Sheldon et al. 1997; Ware et al. 1997), and related neuronal migration disorders were observed in mice deficient in either the cyclin dependent kinase 5 (Cdk5) gene or its neuronal specific activator p35 (Ohshima et al. 1996; Chae et al. 1997). The saga continued recently with reports that mice lacking both the very low density lipoprotein receptor (VLDLR) and the apolipoprotein E receptor 2 (ApoER2) exhibit anatomical trademarks of the reeler brain and that Reln binds directly to these receptors, activating a kinase signaling cascade that leads to tyrosine phosphorylation of Dab1 (D’Arcangelo et al. 1999; Hiesberger et al. 1999; Trommsdorff et al. 1999). These new findings, together with studies on the properties of the proteins encoded by these genes, are elaborating a molecular pathway that directs cell positioning in the developing CNS. The neurological mutant mouse reeler