Genetic and epigenetic mechanisms contribute to motor neuron pathfinding

Many lines of evidence indicate that genetically distinct subtypes of motor neurons are specified during development(1), with each type having characteristic properties of axon guidance and cell-body migration(2). Motor neuron subtypes express unique combinations of LIM-type homeodomain factors that may act as intrinsic genetic regulators of the cytoskeletal events that mediate cell migration, axon navigation or both(3-7). Although experimentally displaced motor neurons can pioneer new routes to their targets(8-11), in many cases the axons of motor neurons in complete isolation from their normal territories passively follow stereotypical pathways dictated by the environment(12-16). To investigate the nonspecific versus genetically controlled regulation of motor connectivity we forced all motor neurons to express ectopically a LIM gene combination appropriate for the subgroup that innervates axial muscles. Here we show that this genetic alteration is sufficient to convert the cell body settling pattern, gene-expression profile and axonal projections of all motor neurons to that of the axial subclass. Nevertheless, elevated occupancy of the axial pathway can override their genetic program, causing some axons to project to alternative targets.