The reeler mouse is a well-known neurological mutant, yet it remains unclear how the absence of Reelin leads to incorrect neuronal positioning during development. Reelin binds to neurons that express the lipoprotein receptors Vldlr and Apoer2, and induces tyrosine phosphorylation of the adaptor protein Disabled1 by Src-family kinases. Thus, the loss of Reelin, both Reelin receptors (Vldlr/Apoer2) or Disabled1 causes similar neuronal positioning errors. Multiple downstream pathways are activated by Disabled1 tyrosine phosphorylation and contribute to functions as diverse as dendritic maturation (Matsuki et al., 2008; Niu et al., 2004) and modulation of synaptic plasticity in adults (Beffert et al., 2005). In this issue of European Journal of Neuroscience, Krüger et al., together with a previous study (Chai et al., 2009), report a novel downstream Reelin pathway that induces the phosphorylation of n-cofilin (p-cofilin) that probably acts upon the actin cytoskeleton of migrating neurons to reduce further movement. During development, neurons migrate in the direction of highly motile filopodia on their leading processes. Cofilin acts to depolymerize F-actin and promote its disassembly, whereas p-cofilin inhibits process extension. What is intriguing about this (Krüger et al., 2010) and the previous study (Chai et al., 2009) is that, despite radically different migratory patterns, spinal cord and cerebral cortical neurons both use Reelin induction of p-cofilin to mediate neuronal positioning. Spinal sympathetic preganglionic and somatic motor neurons initially migrate together from the ventricular zone to form a primitive motor column (Fig. 1A, arrow 1). Somatic motor neurons remain ventrally, whereas sympathetic preganglionic neurons translocate dorsally in a secondary, nonradial migration to the intermediolateral horn (Fig. 1A, arrow 2). Finally, some sympathetic preganglionic neurons migrate medially along radial glia toward the midline (Phelps et al., 1993) (Fig. 1a, arrow 3). In reeler mutants, most sympathetic preganglionic neurons fail to stop in the intermediolateral horn and continue into the midline (Fig. 1B) (Yip et al., 2000; Phelps et al., 2002). Krüger et al. (2010) show that Reelin induces p-cofilin in wild-type and Vldlr mutant sympathetic preganglionic neurons that migrate normally, whereas sympathetic preganglionic neurons in reeler, Apoer2 and Disabled1 mutants do not contain p-cofilin and migrate past their correct positions. The more complex migration in the cerebral cortex is initiated by preplate formation, followed by waves of newly generated neurons that split the preplate and migrate past earlier-born neurons along radial glia, to generate ‘inside-out’ layering (Rakic & Caviness, 1995). Cortical neurons in reeler mutant mice do not split the preplate or migrate past earlier-born neurons. Reelin stabilizes leading processes in vitro (Chai et al., 2009), and yet reeler cortical neurons cease migration too soon, whereas mutant sympathetic preganglionic neurons migrate too far. These distinct positioning errors are probably due to additional factors or cues involved in correct neuronal positioning. Migration of sympathetic preganglionic neurons (SPNs) in wild-type (A) and reeler mutant (B) mice. Initially, SPNs and somatic motor neurons (SMNs) migrate out of the ventricular zone (VZ) together (arrow 1). SPNs then undergo a secondary, nonradial migration toward the intermediolateral horn (arrow 2) and finally a few SPNs migrate back toward the VZ (arrow 3). Reelin-secreting cells, illustrated in red, maintain most wild-type SPNs laterally but, in reeler mutants, the majority of SPNs fail to stop and instead migrate into the midline (arrow 3). IZ, Intermediate Zone; MZ, Marginal Zone. Drawing revised from Kubasak et al. (2004). Future studies will test if other Reelin-sensitive neurons also require p-cofilin for neuronal positioning, or if, for example, only neurons that migrate along radial glia are affected. Do neurons that only express Vldlr receptors use different positioning mechanisms? Based on past experience, additional complexity in how downstream Reelin signaling controls the critical function of neuronal migration may emerge.
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Open Access
Oct 28, 2012
Polyxeni Philippidou + 4
