These cues suppress calpain activity to restore the Sema3B coreceptor Plexin-A1 (Nawabi et al., 2010). Our present data support that gdnf is a key regulator of the activation of the Sema3B repulsive signal. First, gdnf null embryos exhibit defective commissural axon trajectories consistent with such a function. The lack of precrossing defects does not support a role of gdnf in attracting commissural axons toward the FP. Accordingly, in coculture assays, commissural Selleckchem Entinostat axons were not attracted by a gdnf source. This is consistent with studies reporting that Netrin1, Shh, and VEGF mediate together the attractive property of the FP (Charron and Tessier-Lavigne,

2005; Ruiz de Almodovar et al., 2011). Rather, the defects of commissural Cabozantinib chemical structure axons in the FP mimic those of the Sema3B/Plexin-A1 deficiency and are consistent with a repulsive function of gdnf. Nevertheless, we could not evidence any direct repulsive activity of gdnf at basal level and/or after conditioning with FP cues. In contrast,

gdnf could confer a collapse response of commissural growth cones to Sema3B. Second, at a mechanistic level, the calpain activity that silences the sensitivity to Sema3B by processing Plexin-A1 could be suppressed by gdnf. Interestingly, while this property has not yet been reported for gdnf, other neurotrophic factors such as BDNF and NT-3 have been shown in recent work to exert their stimulatory function on axon branching by inhibiting calpain activity (Mingorance-Le Meur and O’Connor, 2009). As expected, gdnf application also resulted in an increase of Plexin-A1 cell surface levels in cultured commissural neurons and fresh commissural tissue. Moreover, FPcm produced from gdnf−/− embryos loses its regulatory activity on growth cone behavior, calpain activity, and Plexin-A1 levels. These findings illustrate a modulatory function for gdnf and an unexpected crosstalk with the Semaphorin signaling. Initially identified as a survival factor, gdnf was reported to play additional important functions in recent

years, contributing to the developmental program of axon growth and navigation. In all cases, gdnf was found to act as either a neurite growth promoter or a chemoattractant for subsets of neuronal projections, such as motor and sensory axons (Schuster et al., 2010; Dudanova et al., Dipeptidyl peptidase 2010). Here we describe an original model system in which gdnf contributes by giving repulsive information for the developing neuronal projections. Contexts other than the FP exist in which coincident expression of gdnf and guidance cues has been reported. Interestingly, another major gdnf source at the dorsal limb was found to cooperate with the Ephrin signaling to control the dorsoventral choice of motor branches in their target limb. This context, however, implicates chemoattractive gdnf activity, which attenuates the repulsive effect of Ephrin ligands (Dudanova et al., 2010).