We conclude

We conclude http://www.selleckchem.com/products/PD-98059.html that Reelin-induced cofilin phosphorylation

is likely to play an important role in the assembly of SPNs in the IMLC. The present results confirm and extend previous studies that showed malpositioning of SPNs in the reeler mutant (Yip et al., 2000, 2009). In wild-type animals, Reelin is present between the central canal and the lateral margin of the spinal cord (Yip et al., 2009). This central location suggested a repulsive activity of Reelin as in the reeler mutant SPNs are not assembled in the IMLC but over-migrate towards the central canal. In line with such a function, ectopic expression of Reelin in neuronal progenitors near the central canal partially rescued the reeler phenotype (Yip et al., 2009). Although these studies pointed to a repulsive effect or stop signal function of Reelin in the migration of SPNs, the underlying molecular mechanisms remained elusive. In the present study, we provide evidence for Reelin terminating the migration process of SPNs by inducing the phosphorylation of cofilin. Cofilin is an actin-associated protein that depolymerizes F-actin find more and thereby provides abundant G-actin molecules for reorganization of the cytoskeleton (Bamburg, 1999). Reorganization of the actin cytoskeleton is required in all processes that involve changes in cell shape. When phosphorylated at serine3,

cofilin is no longer able to depolymerize F-actin, thereby stabilizing the actin cytoskeleton (Arber et al., 1998). By using an antibody specifically raised against p-cofilin, we show in the present study that SPNs in wild-type animals are strongly immunoreactive, whereas they are virtually Methane monooxygenase unstained in reeler mutants, dab1 mutants and mutants lacking ApoER2. Mutants deficient in VLDLR showed a reduced but still recognizable staining for p-cofilin, similar to previous results in the neocortex (Chai et al.,

2009). We conclude from these data that the Reelin-induced phosphorylation of cofilin contributes to the stop signal function of Reelin on SPNs in the spinal cord. In support of this hypothesis, recombinant Reelin added to spinal cord tissue from reeler mutants significantly increased cofilin phosphorylation. In the absence of Reelin, cofilin in SPNs is less phosphorylated and hence the cytoskeleton less stabilized as cofilin continues to depolymerize F-actin, resulting in changes of cell shape and in increased cell motility. Compatible with this hypothesis, SPNs in the reeler mutant over-migrate and occupy territories close to the central canal; their normal assembly in the IMLC does not take place (Yip et al., 2000). Cofilin is a ubiquitous molecule present in many motile cells, and cofilin mutants show severe neuronal migration defects reminiscent of those in the reeler mutant (Bellenchi et al., 2007). We have previously shown that Reelin stabilizes the actin cytoskeleton of migrating neocortical neurons by inducing cofilin phosphorylation (Chai et al., 2009).

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