Manipulating SEMA 3 A signaling using MOLECULAR SCAVENGERS

Abstract

and general discussion 6 136 Chapter 6. The work presented in this thesis illustrates a multi-route approach to studying the role of semaphorin 3A (SEMA3A) in neuromuscular junction (NMJ) plasticity in disease and injury. SEMA3A is a chemorepulsive guidance cue that, during development, plays an important role in guiding neurons to their target. Previous work has identified presymptomatic expression of SEMA3A at the NMJ of G93A-hSOD1 mice (De Winter et al., 2006) giving rise to the hypothesis that it may be acting as a chemorepulsive molecule that induces detachment of the motor neuron from its target in the motor neuron disease Amyotrophic Lateral Sclerosis (ALS). Moreover, several lines of evidence illustrate a potential role for other repulsive axon guidance molecules [such as NOGO-A and/or EPHA4 (Van Hoecke et al., 2012; Jokic et al., 2006)] in the selective denervation at the NMJ in the ALS. In addition, antibodies against SEMA3A have been found in the serum and cerebrospinal fluid of patients with ALS (Hernández et al., 2010). Chapter 1 of this thesis provides an extensive review of how alterations in guidance molecules in ALS could be altering the cytoskeleton at the level of the NMJ to initiate the dying-back phenotype of motor neurons, a pathological feature that may be one of the first signs of the development of ALS (Moloney et al., 2014). To enhance our understanding of how SEMA3A (as a chemorepulsive protein) may fit into the current view of ALS pathophysiology, we used three approaches to manipulate the SEMA3A signaling pathway: 1) MOLECULAR SCAVENGERS (Chapters 2 and 3) We developed soluble NRP1 receptors to scavenge for, and inhibit the function of, SEMA3A both in vitro (Chapter 2) and in vivo (Chapter 3). 2) OVEREXPRESSION (Chapter 4) We used an AAV-mediated overexpression of SEMA3A in skeletal muscle to characterize its effects on NMJ stability and/or motor function. 3) GENETIC MUTATION (Chapter 5) We used a transgenic mouse line harboring a SEMA3A mutation that decreases the chemorepulsive properties of the protein and characterized the effects of reduced SEMA3A signaling on sprouting after injury, or on ALS-induced motor deficits. 137 6 Summary and general discussion

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@inproceedings{MoloneyManipulatingS3, title={Manipulating SEMA 3 A signaling using MOLECULAR SCAVENGERS}, author={Elizabeth B Moloney and Fred de Winter and Joost Verhaagen} }