, 2000). This combinatorial signaling is likely critical in several developmental contexts. For example, previous studies have shown that nectin1 is expressed in hippocampal mossy fibers, whereas nectin3 is expressed in CA3 pyramidal neurons. These nectins are localized at SCH 900776 price synaptic contacts

formed between the two cell types, and perturbation of their function leads to synaptic defects (Honda et al., 2006). Cdh2 is also recruited to the synaptic sites and is required for their function (Brigidi and Bamji, 2011), suggesting that cooperation between nectins and cadherins determines synaptic specificity. However, in some instances, nectins appear to function independently of cadherins. For example, nectin1 and nectin3 regulate pathfinding of commissural axons at the spinal cord midline independently of cadherins (Okabe et al., 2004). Instead, axonal pathfinding depends on the secreted signaling molecule netrin1 (Serafini et al., 1994). Nevertheless, there is a striking similarity between axonal pathfinding and radial neuronal migration Decitabine in that directional motility in both cases is regulated by combinations of secreted signaling molecules, such as reelin and netrin1, together with cell adhesion molecules, such as nectins and cadherins. The combinatorial code of these molecular cues likely varies depending on the

cell type and developmental context, resulting in different functional outputs. In this regard, it will be interesting to analyze nectin and cadherin functions during other stages of neocortical development, for example during the formation of axonal processes or dendrites within neocortical cell layers. Mice with mutations

in nectin1 and nectin3 show defects in hippocampal synapse formation, but no neocortical defects have been reported in these mice when analyzed by general histology ( Honda et al., 2006). In light of the current findings, it will be important to analyze the formation Terminal deoxynucleotidyl transferase of neocortical cell layers in these mice further, for example by using molecular markers that define the identity and position of subtypes of projection neurons. In addition, it is feasible that in these knockout mice, which lack nectin1 or nectin3 throughout development, other cell adhesion molecules might be upregulated to functionally compensate for the loss of nectin1 and nectin3. This compensation may not be triggered by acute perturbations. Similar observations have been made in other instances, for example when the function of doublecortin was disrupted genetically or by RNAi. Only in the latter case were functional defects observed ( Bai et al., 2003), whereas defects following genetic perturbation were compensated for, at least in part, by expression of doublecortin kinase ( Deuel et al.