Therefore, Reelin can switch the adhesion molecules to mediate the dual functions of Rap1 in neuronal migration. In addition, given the idea that translocation is the phylogenetically conserved see more radial glia-independent mode of migration (Nadarajah et al., 2001) as compared to the evolutionally acquired radial glia-guided locomotion (Rakic, 1972), it is easy to conceive that different adhesion molecules are involved in the different migratory modes,

i.e., N-cadherin for locomotion (Kawauchi et al., 2010) and integrin α5β1 for terminal translocation. We demonstrated that constitutively active integrin α5 could rescue the terminal translocation failure, cooperatively with Akt, in Reelin receptors-knockdown neurons. However, we also observed that cotransfection of the mutated integrin α5 and Akt could not rescue the Dab1-knockdown phenotype (data not shown). One explanation for this failure is that Dab1 itself may be involved in the regulation of integrin functions through interaction between its PTB domain and the NPxY motif of integrin β1 (Schmid et al., 2005). An alternative explanation is that Dab1 may regulate some cellular functions independent of Reelin stimulation (Honda et al., 2011). We also failed to rescue the migration failure in the reeler mutant cortex by cotransfection of CA-integrin α5 and Akt (data not shown). Although there is no obvious PCZ-like

structure in the reeler cortex ( Sekine et al., 2011), a previous selleck screening library study using Dab1 chimeric mice showed that most Dab1 +/+ cells could migrate in the Dab1 −/− environment ( Hammond et al., 2001). In addition, another study using ectopic expression of Reelin in the VZ showed partial rescue of migration of some neurons during preplate splitting ( Magdaleno et al., 2002). Because integrin α5β1-dependent terminal translocation is the specific migration mode around the PCZ in the wild-type cortex, it is possible that the abnormal layering in the reeler cortex was caused or modified by 17-DMAG (Alvespimycin) HCl other/additional mechanisms including, for example, abnormal formation of the internal plexiform zone in the reeler cortex ( Tabata and

Nakajima, 2002). Future studies using genetically engineered mice will be needed to fully address the role of Reelin-induced integrin activation for the layer formation. Terminal translocation is thought to share some mechanisms with somal translocation of the earliest-born neurons (Nadarajah et al., 2001). A recent study showed that N-cadherin is required for somal translocation (Franco et al., 2011). However, N-cadherin regulation by Reelin during somal translocation was not directly shown, and it was described that Dab1 null migration phenotype was not rescued by overexpression of N-cadherin. Consistently, we also observed that N-cadherin alone was not sufficient to rescue the terminal translocation failure observed after transfection of DN-C3G.