Mechanisms and molecules in motor neuron specification and axon pathfinding

The vertebrate nervous system performs the most complex functions of any organ system. This feat is mediated by dedicated assemblies of neurons that must be precisely connected to one another and to peripheral tissues during embryonic development. Motor neurons, which innervate muscle and regulate autonomic functions, form an integral part of this neural circuitry. The first part of this review describes the remarkable progress in our understanding of motor neuron differentiation, which is arguably the best understood model of neuronal differentiation to date. During development, the coordinate actions of inductive signals from adjacent non-neural tissues initiate the differentiation of distinct motor neuron subclasses, with specific projection patterns, at stereotypical locations within the neural tube. Underlying this specialisation is the expression of specific homeodomain proteins, which act combinatorially to confer motor neurons with both their generic and subtype-specific properties. Ensuring that specific motor neuron subtypes innervate the correct target structure, however, requires precise motor axon guidance mechanisms. The second half of this review focuses on how distinct motor neuron subtypes pursue highly specific projection patterns by responding differentially to spatially discrete attractive and repulsive molecular cues. The tight link between motor neuron specification and axon pathfinding appears to be established by the dominant role of homeodomain proteins in dictating the ways that navigating motor axons interpret the plethora of guidance cues impinging on growth cones.