Ross, AJ; (2015) Multiple roles of integrin-α3 in the development and maintenance of the neuromuscular junction. Doctoral thesis , UCL (University College London).

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Abstract

The neuromuscular junction (NMJ) is the synaptic contact between motoneurons and muscle, where neurotransmission results in the contraction of the muscle fibres. The basal lamina instructs NMJ development at virtually every stage. Largely, the functions of the basal lamina are mediated through interactions with cell surface adhesion receptors; however, less is known about the identities and roles of these at the NMJ. Integrin-α3 is an extracellular matrix receptor that has previously been identified at the NMJ active zones, the sites of neurotransmitter release in the presynaptic terminus. As integrin-α3 binds to laminin-α4 and other active zone components, my hypothesis is that it may be important for relaying signals provided by the basal lamina during NMJ development. In this study, the integrin-α3 knockout mouse was used to explore the functions of this protein at the NMJ. Mutants displayed defects in active zone assembly and developmental motoneuron patterning. NMJs frequently resembled those found in aged animals, and in some cases, nerve terminals were detached from the synaptic cleft. Finally, electrophysiological analysis revealed defects in neurotransmission at mutant NMJs, including reduced efficiency of synaptic vesicle release, and impaired sensitivity of nerve terminals to external Ca2+. Previous studies have implicated integrin-α3 in muscle development; however, I find no expression of integrin-α3 in the muscle, and no defects in myogenesis in integrin-α3 mutants. These results indicate multiple roles for integrin-α3 at the NMJ, for active zone assembly, adhesion of nerve terminal, morphological integrity and neurotransmission. To my knowledge, this study identifies for the first time a cell surface receptor for the anchorage of pre- and postsynaptic elements at the NMJ. These results suggest that alterations in integrin-α3 expression or function may underlie some of the changes associated with ageing at the NMJ, and that mutations in its encoding gene may cause myasthenic syndromes.

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