Much progress has been made in this area during the last decade when genomic and proteomic data from cellular proteins are compared. In the case of secreted proteins, especially those expressed by multiple tissues, such connections are even harder to make

of upregulated FGFR-1 in SMA-mice spinal cords might point towards SMNdependent guidance and outgrowth defects. Interestingly, a zebrafish model of SMA with a SMN-reduction in single motoneurons leads to axonal outgrowth and guidance defects. Moreover, we could recently show SMN-dependent changes in actin-dynamics and signaling pathways controlling neurite outgrowth. FGFR-1 is known to act via two pathways on neurite outgrowth, MEK/ERK and PI3K/Akt. Consistent with our findings of February 2012 | Volume 7 | Issue 2 | e31202 The FGF-System in SMA an FGFR-1 upregulation both, Akt and ERK were hyperphosphosphorylated in NSC34 cells under SMN-knockdown. In PC12 cells, FGFR activation leads to a sustained ERK-activation and subsequently to neurite outgrowth. PI3K/Akt and MEK/ERK pathways are both necessary for neurotrophic factor mediated axonal outgrowth. Neurotrophic signaling, mediated by PI3K/Akt and MEK/ERK-pathways, finally activates transcription factors promoting neuronal differentiation as well as they directly signal to small GTPases Rac, Cdc42 and RhoA upstream of rho kinase . In an intermediate SMA-mouse model, an inhibition of ROCK leads to improved NMJ-maturation and increased lifespan. Moreover, our group could demonstrate changes in F-/G-actin ratios under SMN knockdown conditions in PC12 cells and motoneurons of SMA mice. Mechanistically, we could identify Profilin2a as a binding partner of the SMN-protein. Since Prof2a also binds to ROCK, it links SMN-reduction with dysregulation of actin-dynamics. Moreover, we could show widespread dysregulations within the signaling network regulating actin-dynamics 474-58-8 leading to neurite outgrowth inhibition. Thereby, SMN reduction causes a release of Prof2a from SMN-Prof2a complex which in turn binds ROCK inducing a sequestration of ROCK from other downstream targets. Interestingly, the ROCK pathway is also linked to the MEK/ERK-pathway. In PC12 cells, an inhibition of ROCK leads to enhanced FGFR induced ERK-phosphorylation, which does not “1635054 occur without ” any FGFR stimulus. Similarly, a stimulus by ciliary neurotrophic factor and a simultaneous inhibition of ROCK results in hyper-phosphorylated ERK1/2 in retinal ganglion cells and in a Akt hyper-phosphorylation. Thus, a sequestration of ROCK by enhanced Prof2a binding under SMN reduction and a simultaneous FGFR-1 upregulation explain the sustained ERK and Akt-phosphorylation observed in this study. While a transient ERK activation promotes neuronal survival, a sustained ERK activation might cause cell death suggesting a role of ERK in neurodegenerative processes. Interestingly, our findings of upregulated FGFR-3c and FGF-2 also match a cell death promoting pattern. Both, FGFR-3 and FGF-2 knockout mice show less apoptosis of spinal ganglia sensory neurons after sciatic nerve axotomy implicating a negative modulating role of the FGFR-3/FGF-2 interaction on survival in neurodegenerative processes. In accordance with that, apoptosis in retina cell development is induced by FGF-2. Moreover, FGF-9, which we could show to be downregulated in SMA-mice spinal cords, is known to be expressed in human and rat motoneurons and in vitro experiments reveal a survival promoting role of FGF-9 on motoneurons. Taken together, we could show widespread alterations within the FGF-system of SMA-mice muscle and spinal cords. Dysregulations in muscle might be associated with muscle-intrinsic functions such as myotube differentiation but also with NMJmaintenance defe