Stromal cell-derived factor-1 and hepatocyte growth factor guide axon projections to the extraocular muscles

Vertebrate eye movements depend on the co-ordinated function of six extraocular muscles that are innervated by the oculomotor, trochlear, and abducens nerves. Here, we show that the diffusible factors, stromal cell-derived factor-1 (SDF-1) and hepatocyte growth factor (HGF), guide the development of these axon projections. SDF-1 is expressed in the mesenchyme around the oculomotor nerve exit point, and oculomotor axons fail to exit the neuroepithelium in mice mutant for the SDF-1 receptor CXCR4. Both SDF-1 and HGF are expressed in or around the ventral and dorsal oblique muscles, which are distal targets for the oculomotor and trochlear nerves, respectively, as well as in the muscles which are later targets for oculomotor axon branches. We find that in vitro SDF-1 and HGF promote the growth of oculomotor and trochlear axons, whereas SDF-1 also chemoattracts oculomotor axons. Oculomotor neurons show increased branching in the presence of SDF-1 and HGF singly or together. HGF promotes the growth of trochlear axons more than that of oculomotor axons. Taken together, these data point to a role for both SDF-1 and HGF in extraocular nerve projections and indicate that SDF-1 functions specifically in the development of the oculomotor nerve, including oculomotor axon branch formation to secondary muscle targets. HGF shows some specificity in preferentially enhancing development of the trochlear nerve.