Two motor axons expressing different coloured fluorescent proteins (yellow and cyan). Post-synaptic receptor sites are labelled with Alexa-594 conjugated bungarotoxin (red). Reproduced, with permission, from Nature © Macmillan Magazines Ltd.

In mammals, the immature neuromuscular junction (NMJ) receives inputs from several motor neurons, but these are gradually whittled away during early postnatal life, so that each muscle fibre in the adult is innervated by a single motor neuron (although each motor neuron can still innervate many muscle fibres). What determines which input will escape elimination? Is the competition mediated by local factors at each NMJ, or by some global property of the motor neuron? Two new studies reported in Nature provide some answers to these questions.

Kasthuri and Lichtman generated transgenic mouse lines in which a fraction of motor neurons expressed different fluorescent proteins. They obtained mice in which a single forelimb motor neuron expressed cyan fluorescent protein, whereas another expressed yellow fluorescent protein. In the forelimb muscles of neonatal mice, the authors studied NMJs that contained one input from each labelled neuron. Interestingly, they found that if the 'cyan' input won the competition against a 'yellow' axon at one NMJ, it also beat the yellow input at all the other NMJs that were co-innervated by these two neurons. However, this did not mean that the outcome for these two axons would be the same against all competitors, and by bringing a third neuron into the equation, the authors could establish a competitive hierarchy.

So what gives a motor neuron the competitive edge? In a second study, Buffelli and colleagues showed that synaptic efficacy might be a defining factor. They reduced neurotransmission in some motor neurons by conditionally knocking out the gene for choline acetyltransferase (ChAT). In the absence of competition, the ChAT-negative axons could readily make synapses with muscle fibres, but their inputs were always eliminated when they were pitted against wild-type inputs.

In addition, Kasthuri and Lichtman showed that the ranking of a motor neuron in the competitive hierarchy was inversely proportional to the size of its axonal tree. Taken together with the findings of Buffelli et al., this might imply that each neuron has a finite supply of neurotransmitter, which is spread more thinly as the size of the motor unit increases.

These findings highlight the benefits of looking at the bigger picture to make sense of events at individual synapses. Manipulations such as knocking out the ChAT gene create abnormally large imbalances in synaptic efficacy, and it remains to be seen whether natural variations in neurotransmission are sufficient to drive competition at the NMJ, or whether it requires additional factors that are globally distributed in motor neurons.