Targeting of the EphA4 tyrosine kinase receptor affects dorsal/ventral pathfinding of limb motor axons

The Eph family of tyrosine kinase receptors has recently been implicated in various processes involving the detection of environmental cues such as ax onal guidance, targeted cell migration and boundary formation. We have inac tivated the mouse EphA4 gene to investigate its functions during developmen t. Homozygous EphA4 mutant animals show peroneal muscular atrophy correlati ng with the absence of the peroneal nerve, the main dorsal nerve of the hin dlimb, This phenotype is also observed, although with a lower penetrance, i n heterozygotes. During normal hindlimb innervation, motor axons converge t owards the sciatic plexus region at the base of the limb bud, where they mu st choose between dorsal and ventral trajectories within the limb. Among th e axons emerging from the sciatic plexus, dorsal projections show higher le vels of EphA4 protein than ventral axons, In EphA4 mutant mice, presumptive dorsal motor axons fail to enter the dorsal compartment of the limb and jo in the ventral nerve. Our data therefore suggest that the level of EphA4 pr otein in growing limb motor axons is involved in the selection of dorsal ve rsus ventral trajectories, thus contributing to the topographic organisatio n of motor projections.