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A balancing act for axonal outgrowth and synaptic differentiation at the neuromuscular junction

Authors Meng, Min
Issue Date 2010
Summary During the development of the vertebrate neuromuscular junction (NMJ), growing motor axons come into contact muscle and differentiate into specialized presynaptic terminals that secrete the neurotransmitter acetylcholine (ACh), which activates ACh receptors (AChRs) clustered in the postsynaptic muscle membrane to trigger contraction. Although it is well known that the survival and growth of neurons are promoted by the factors named neurotrophins (NTs), it is unclear how growing axons stop upon reaching their muscle targets to establish stable synaptic contacts. Intriguingly, previous work from our group showed that the addition of NTs to Xenopus nerve-muscle co-cultures enhanced neuronal survival but actually inhibited synaptogenesis. What are the molecular cues furnished by the surface of muscle that instruct a contacting axon to stop growing and start to differentiate? What are the molecules in neurons that enables them to make a “growth-to-synaptogenesis” switch? These issues relating to the initiation phase of NMJ assembly were critically investigated in my thesis research using molecular and cell biological approaches. The findings in this thesis suggested that, one, elevated NT-signaling in neurons can disrupt stable nerve-muscle interaction and inhibit NMJ assembly. Thus, the effects of the NTs must be offset to allow NMJ development to begin. Two, elevation of intrinsic p75NTR signaling can counterbalance the growth promoted by NT/ Trk-signaling, which can enable the neurons to stop and enter a synaptogenic state. And, three, in addition to NT that enhance the survival and growth of motor neurons, the surface of muscle provides to the neurons factors such as galectin-1, which can allow the motor axons which touch muscle to make the growth-to-synaptogenesis transition needed for the initiation of NMJ assembly.
Note Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2010
Language English
Format Thesis
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