ated in less affected muscles during disuse-mediated skeletal muscle atrophy. In vivo overexpression of FGFR-1 protects from myofibre size decrease. Interestingly, SMN-knockdown in C2C12 cells leads to reduced proliferation as well as defects in myoblast-fusion. Moreover, SMA-fetus predicted to develop SMA-type I, show a delay in growth and maturation of myotubes prior to morphological changes occurring in spinal cords. Thus, FGFR-1 and 4 downregulations in SMA-mice might fulfill negative modulating roles in myotube differentiation and muscular atrophy. However, although there is still an ongoing debate whether changes in muscle occur as a result of changes in motoneurons or denervation, there is growing evidence of a muscle intrinsic pathology in SMA. On a cellular level, the SMN-complex localizes to sarcomeric Z-discs both in Drosophila and mice. A role of the SMN-complex in Z-disc integrity, signaling to the nucleus and/or mRNP transport was suggested. Moreover, recent 6 February 2012 | Volume 7 | Issue 2 | e31202 The FGF-System in SMA findings in a SMA mouse model comparing affected and unaffected muscles point to a muscle intrinsic pathology of SMA involving cellular survival pathways. Interestingly, a muscular overexpression of insulin like growth factor 1, which is known to lead to muscle-hypertrophy, also increases muscle mass in SMA-mice and enhanced survival rates. Several publications in recent years suggested an impaired muscle-dependent maturation and maintenance of the neuromuscular junctions during postnatal development in SMA. Muscle specific “1656303 reduction of SMN resulted in lower numbers of synaptic boutons at the NMJ and a muscular SMN-rescue improved survival of SMA Drosophila models. In vitro experiments show that SMA-patient derived muscle cells are less capable of preventing apoptosis of rat primary motoneurons than controls. These results indicate an impaired motoneuronmuscle communication caused by reduced SMN-levels in muscle cells leading to cell death in motoneurons. Remarkably, SMNknockdown in Drosophila leads to reduced mRNA levels of the FGFR orthologue heartless in larval brains. Moreover, a mesodermspecific SMN-knockdown results in a reduction of postsynaptic accumulation of htl and a reduced number of synaptic boutons which could be rescued by mesoderm-specific overexpression of htl. Importantly, the SMN-dependent reduction of htl in Drosophila is consistent with our findings of down-regulated FGFRs in SMA-mice muscle. However, as Drosophila only expresses two FGFRs and three ligand orthologues, these results are difficult to compare to mice. A possible role of postsynaptically expressed FGFRs in NMJ integrity of mice has not yet been investigated. In spinal cord, we could show alterations of 4 receptors and 3 ligands. Importantly, the upregulation of FGFR-1 in spinal cord could be observed at the pre-symptomatic 
stage P1. NSC34 cells under SMN-knockdown resemble this regulation and show a sustained ERK1/2-activation. Expression of FGFR-1, which selectively signals through MAPK/ERK in vitro, is crucial for fiber outgrowth and guidance. FGFR-1 knockout motoneurons transplanted into neural tube of chicken embryos show severe guidance defects. Importantly, motoneurons transfected with constitutively active MEK, an upstream activator of ERK, also showed defects in axonal guidance. “
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