Such studies may be of particular relevance to SMA where it is quite difficult to discern the developmental consequences of SMN loss in humans, as neurodegenerative symptoms displayed by patients may obscure basic problems resulting from altered developmental programs such as neuronal pathfinding, initial NMJ formation, etc (Simic et al., 2008; Liu et al., 2010). In vertebrates, synaptic development and maintenance use at least three distinct signaling mechanisms: the TGF-, CIT have identified elements of all three of these pathways as modifiers of may serve as a node, integrating signaling events crucial for NMJ function, potentially leaving this structure particularly vulnerable to the loss of Smn. though SMA is caused by mutations that impair function, the severity of the disease is modulated by copy number, which varies in the human population (McAndrew et al., 1997). As copy number increases, the amount of full-length SMN protein also increases, rendering loss of less pathogenic. Therefore, cellular processes as well as single genes capable of augmenting SMN protein activity may be therapeutically relevant. To identify such processes/targets and gain insights into fundamental Racecadotril (Acetorphan) aspects of SMA, several different organisms, including genome encodes a single orthologue of SMN, the Survival motor neuron (Smn) protein, which is ubiquitously expressed and localizes to nuclear gems (Chan et al., 2003; Liu et al., 2006; Chang et al., 2008), similar to the distribution observed in vertebrates (Monani, 2005). In loss-of-function mutations result in reduced viability and decreased motility as well as muscular atrophy in the adult thorax, phenotypes analogous to the human pathology (Chan et al., 2003; Rajendra et al., 2007; Chang et al., 2008). Moreover, neuromuscular junction (NMJ) defects are associated with both vertebrate and invertebrate models (Chan et al., 2003; Chang et al., 2008; Kariya et al., 2008). In addition to its canonical subcellular distribution, Smn is also clearly concentrated in the postsynaptic region of the larval NMJ (Chang et al., 2008) and has been reported to localize to sarcomeres of adult myofibrils (Rajendra et al., 2007). Despite this, tissue-specific reduction of Smn demonstrates that normal NMJ morphology requires activity in both muscles and neurons (Chang et al., 2008). Finally, an observation of critical importance to the model is that the morphology and the physiology of the NMJ are sensitive to levels of Smn (Chang et al., 2008; unpublished data), mirroring the dosage dependence observed Racecadotril (Acetorphan) in SMA patients. Racecadotril (Acetorphan) Taking advantage of the dosage sensitivity of loss-of-function phenotypes, we performed systematic genetic screens to identify modifiers of activity (Chang et al., 2008). Among the genes identified in this manner was the locus, which encodes one of the two FGF receptors (Glazer and Shilo, 1991). In general, the FGF pathway has been demonstrated to be involved in a diverse range of cellular and developmental processes, including proliferation, migration, differentiation, and apoptosis (Itoh and Ornitz, 2004; Huang and Stern, 2005). In nervous system remains poorly characterized (Garca-Alonso et al., 2000; Forni et al., 2004). In this study, we investigate the relationship between and several components of the FGF pathway, demonstrating a clear link between and FGF. Epistasis analysis reveals that regulates FGF signaling output, and molecular studies indicate that activity influences FGF receptor transcript levels. Furthermore, we show that activation of FGF signaling can restore (FGF receptors, was identified in a genetic screen as a modifier of mutations on (alleles (as a bona fide modifier of loss-of-function mutations, thereby validating our initial observations. Open in a separate window Figure 1. Multiple FGF pathway components modify ((((((Vincent et al., 1998), which regulates the phosphatase ((alleles suppress the lethal phenotype. Significant differences are indicated (*, P 0.05; **, P Racecadotril (Acetorphan) 0.01). If, as the above analysis of implies, FGF signaling can modulate activity, we expect other genetic elements of the FGF pathway to behave as modifiers as well. We chose to examine this relationship in the mesoderm, as the activity of the FGF signaling pathway has been shown to be important for the development and the maintenance of muscles (Shishido et al., 1993; Beiman et al., 1996; Gisselbrecht et al., 1996; Michelson et al., 1998; Vincent et al., 1998; Schulz and Gajewski, 1999; Stathopoulos et al., 2004). The mesoderm-specific driver was used to control expression of inducible RNAi transgenes that specifically target either.