SDF-1 is a chemokine—a peptide that attracts leukocytes by activating a G protein signaling cascade. In contrast, neuronal guidance molecules such as the netrins, ephrins, and Slit are proteins that bind single transmembrane receptors linked to a variety of downstream signaling pathways. The two worlds were bridged last year when Rao found that the neuronal repellant Slit could also inhibit leukocyte chemotaxis. Now, he has completed the loop by confirming SDF-1's function in the brain.
This function was suspected when immunologists made mice lacking SDF-1 and noted a cerebellar defect, whereas others showed that SDF-1 affected either chemotaxis or the motility level of neurons. In Rao's experiments, collagen blocks embedded with SDF-1 attracted embryonic neuronal precursor cells, and the meninges (the outside lining of the brain) attracted the cells only if the gene encoding SDF-1 had not been knocked out. The meninges thus uses SDF-1 to attract the cells before they go on to form structures involved in motor control and other functions.
The two worlds of chemokines and neuronal guidance may have arisen, says Rao, because “if your assay is set up in a particular way, you get what you are looking for.” But now he thinks that factor participation in both immune and nervous systems will turn out to be “a common thing.” The next place to look may be in blood vessels. Slit is expressed in the endothelium, so it may keep noninflammatory immune cells from escaping the blood. ▪