How is the growth of a synaptic arborization controlled? This question has important implications for the function of neural circuits, because the shape and size of the arborization strongly influences the number and strength of connections that a neuron makes with its targets. In a recent paper in Neuron, Sweeney and Davis report on the characterization of spinster (spin), a gene that encodes a negative regulator of synaptic growth, and they provide an intriguing insight into the role of protein trafficking in the control of synaptic morphology.

In Drosophila, the spin mutation was initially identified for its effects on courtship behaviour. Sweeney and Davis showed that loss of spin function also causes synaptic overgrowth at the neuromuscular junction (NMJ), with some axons producing more than double their usual number of boutons. spin seems to function both pre- and postsynaptically, as restoring expression at only one of these sites produced only a partial rescue of the overgrowth phenotype.

The explanation for this phenotype came from two seemingly disparate sets of observations. First, the authors found that Spin — a transmembrane protein with sequence homology to monoamine transporters — localizes to the late endosomal/lysosomal compartment in both the neuron and the postsynaptic muscle fibre. These subcellular compartments were enlarged in the spin mutant, and they also showed abnormal architecture. In addition, there was evidence for defects in lysosomal clearance.

Second, previous studies have implicated transforming growth factor-β (TGF-β) in the regulation of synaptic growth. In these new experiments, Sweeney and Davis decreased TGF-β signalling with receptor mutations, and they showed that this reduced synaptic overgrowth in the spin mutants. They also increased the levels of TGF-β signalling by blocking the activity of the inhibitory molecule Daughters against Dpp (Dad). They found that this manipulation produced a synaptic overgrowth phenotype similar to that seen in the spin mutants.

How can these observations be reconciled to produce a model of Spin function? The late endosomal compartment is the site of a crucial protein trafficking decision — whether to recycle internalized receptors back to the cell surface, or send them to the lysosome for degradation. Sweeney and Davis propose that spin is necessary for the proper execution of this trafficking decision and that in its absence, there is enhanced signalling, either due to increased sorting of receptors to the cell surface, or inefficient degradation of receptors in the lysosome.

So, this study provides evidence that misregulated growth factor signalling, resulting from defects in endosomal trafficking, can cause synaptic overgrowth. These findings might have implications for lysosomal storage diseases in humans, such as Batten's disease. Neurodegeneration is a frequent characteristic of these diseases, but it has not been clear how this relates to the defects in lysosomal function. The spin mutant provides us with new possibilities for exploration.