A Review of the Mechanisms Modulating Neuromuscular Junction Assembly

Abstract

Synaptogenesis of the neuromuscular junction (NMJ) can be divided into 3 main processes - prepatterning, patterning of the pre- and postsynaptic membranes and maturation. Prepatterning, the formation of aneural acetylcholine receptor (AChR) clusters, is mediated by Wnt 11r that is secreted from the motor neuron. Later, patterning is guided by secreted and transmembrane signalling molecules. After release into the synaptic cleft, the former become integrated into the synaptic basal lamina. They include Agrin, fibroblast growth factor (FGF) 7/10/22 and laminin β2. Agrin is responsible for the formation of AChR neural clusters in the postsynaptic membrane. FGF and laminin β2 signalling are involved in the patterning of the presynaptic membrane as they are required for the clustering of synaptic vesicles and active zone maintenance/growth, respectively. A transmembrane adhesion molecule important for NMJ synaptogenesis is neural cell adhesion molecule (NCAM). Intracellular NCAM signalling supports the accumulation of synaptic vesicle proteins at the presynaptic terminal and confines vesicle cycling to the active zones by downregulating the immature vesicle-cycling-transmitter release system. Finally, maturation processes follow, one being the elimination of inactive synapses. The cytokine tumour necrosis factor α (TNFα) has been proposed as a retrograde signal involved in this process.