Altogether, these data support a model whereby gdnf and NrCAM act together to control the acquisition of a repulsive response to Sema3B, which contributes to guide commissural growth cones across the FP. Additional investigations selleck screening library are required to define the exact contribution of each cue, which could underlie the distinct outcome of their invalidation in mice. Several hypotheses can be drawn. First, apart from regulation of Plexin-A1 levels, additional signaling differences between the two cues might be at play to explain the differences. For example, the prominent stalling observed in context of NrCAM deficiency could reflect a contribution of NrCAM in contact interactions

engaging the growth cone with FP cells, as reported in the chick model ( Stoeckli and Landmesser, 1995). Second, distinct www.selleckchem.com/products/MLN8237.html expression levels and/or distribution profiles of NrCAM and gdnf could concentrate their action at a distinct step of the FP crossing. Likewise,

NrCAM loss could essentially affect commissural axon guidance within the FP where the cue might be highly concentrated, whereas gdnf loss would also affect the turning decision at the FP exit, due to larger range of diffusion. Third, in the NrCAM- and gdnf-deficient embryos, the duration of FP crossing could differ. NrCAM loss could slow down the progression of the growth cone, allowing longer exploration and favoring appropriate turning choices. Conversely, in context of gdnf loss, the progression could be unaffected, favoring turning errors. Finally, a hierarchy between gdnf and NrCAM could exist, with NrCAM being only required for reinforcing the gdnf action very locally within SB-3CT the FP, where the sensitization process is taking place. Whatever the case, our study identifies unexpected cooperation between a cell adhesion molecule

and a neurotrophic factor in the regulation of axon path finding. It also provides evidence supporting that complex interplays between different molecular signaling are crucial for the control of guidance choices at critical steps of axon navigation, such as midline crossing. Finally, Shh was reported in previous work to activate the Sema3B midline signaling (Parra and Zou, 2010). In our neuronal cultures, Shh application failed to confer a Sema3B-induced collapse response of commissural neurons. Our observation that the loss of both gdnf and NrCAM fully recapitulate the spectrum of phenotypes resulting from Sema3B/Plexin-A1 deficiency indicates that gdnf and NrCAM are the major triggers of the repulsive Sema3B midline signaling. Thus, if Shh plays a role in this regulation, then it might not be able to compensate in vivo the lack of NrCAM and/or gdnf, as its expression pattern was not altered by gdnf and NrCAM deficiencies ( Figure 1H, Figure S3D). Genotyping of NrCAM mouse line was performed as described in Sakurai et al. (2001).