What are they? Netrins are a conserved family of secreted proteins that guide migrating cells and axonal growth cones. The name is derived from the Sanskrit ‘netr’, meaning ‘one who guides’. They are 70–80kDa in size, with some homology to laminin, including a series of three EGF-like repeats. There is one netrin in worms, two in flies, and at least two each in chicks, mice and men. How where they found? It was one of those wonderful times when invertebrate genetics and vertebrate biochemistry converged upon the same protein family. The first netrin to be identified was the C. elegans UNC-6 protein, which is required for axons to grow along the dorsal–ventral body axis. The function of UNC-6 as a guidance cue was not fully appreciated however until Marc Tessier-Lavigne and colleagues purified two related proteins from chick brains based on their ability to promote the outgrowth and turning of vertebrate spinal cord axons. What do they do? The best known role of netrins is to attract commissural axons towards the CNS midline. These are the axons that connect the two halves of the nervous system so that each side of the body knows what the other is doing or thinking. Netrins are expressed at the midline of all bilaterally symmetric animals studied so far. Do jellyfish and hydra have netrins? Whether radially symmetric organisms also have netrins is still an open question, but it is a fairly safe bet that they do. Netrins have other functions as well, such as stimulating axon outgrowth. So even if they don't have commissures, jellyfish probably still need netrins to help their axons grow. Are netrins always so attractive? No, they can be repulsive as well. There are at least three ways in which their ‘come here’ signal can be turned into a ‘go away’ signal: changing the axon's receptors, changing the substrate, and changing the levels of intracellular cAMP. Repulsion by netrins may be important in the CNS to direct at least some motor axons away from the midline, sending them off in search of their peripheral muscle targets. How do axons sense netrins? There are two main families of netrin receptors, the DCC and UNC5 families. Both are single-pass transmembrane receptors of the Ig superfamily. UNC5 receptors mediate repulsive netrin signalling. DCC receptors are required mainly for attraction, but are also co-receptors for repulsion once axons get further away from the netrin source. How do these receptors signal to the cytoskeleton? This is still mostly a mystery. The cytoplasmic domains of DCC and UNC5 receptors don't have an obvious catalytic activity, so presumably they recruit other proteins to activate signal transduction. The usual suspects for intracellular signalling have all been rounded up — second messengers, small G proteins, calcium, phospho-lipids — and even some unusual suspects such as new protein synthesis, but none of them has yet been convicted. Where can I find out more?