Foxp1 and Lhx1 Coordinate Motor Neuron Migration with Axon Trajectory Choice by Gating Reelin Signalling

Topographic neuronal maps arise as a consequence of axon trajectory choice correlated with the localisation of neuronal soma, but the identity of the pathways coordinating these processes is unknown. We addressed this question in the context of the myotopic map formed by limb muscles innervated by spinal lateral motor column (LMC) motor axons where the Eph receptor signals specifying growth cone trajectory are restricted by Foxp1 and Lhx1 transcription factors. We show that the localisation of LMC neuron cell bodies can be dissociated from axon trajectory choice by either the loss or gain of function of the Reelin signalling pathway. The response of LMC motor neurons to Reelin is gated by Foxp1- and Lhx1-mediated regulation of expression of the critical Reelin signalling intermediate Dab1. Together, these observations point to identical transcription factors that control motor axon guidance and soma migration and reveal the molecular hierarchy of myotopic organisation. Many areas of our nervous system are organized in a topographic manner, such that the location of a neuron relative to its neighbors is often spatially correlated with its axonal trajectory and therefore target identity. In this study, we focus on the spinal myotopic map, which is characterized by the stereotyped organization of motor neuron cell bodies that is correlated with the trajectory of their axons to limb muscles. An open question for how this map forms is the identity of the molecules that coordinate the expression of effectors of neuronal migration and axonal guidance. Here, we first show that Dab1, a key protein that relays signals directing neuronal migration, is expressed at different concentrations in specific populations of limb-innervating motor neurons and determines the position of their cell bodies in the spinal cord. We then demonstrate that Foxp1 and Lhx1, the same transcription factors that regulate the expression of receptors for motor axon guidance signals, also modulate Dab1 expression. The significance of our findings is that we identify a molecular hierarchy linking effectors of both neuronal migration and axonal projections, and therefore coordinating neuronal soma position with choice of axon trajectory. In general, our findings provide a framework in which to address the general question of how the nervous system is organized.