Spinal Cord Meninges Produce Attractive and Repellent Cues for Developing Axons

The meninges are connective tissue layers that envelop vertebrate brain and spinal cord. The meninges protect the central nervous system (CNS), contribute to the circulation of cerebrospinal fluid, and provide a structural framework for blood vessels entering the CNS. Recent work provides evidence that the meninges also fulfill critical functions during the development of the CNS by regulating both neural progenitor generation and migration. During development the majority of neurons within the CNS have axonal projections that remain within the CNS. However, there are unique populations, including motor and sensory neurons, which cross the boundary between the CNS and peripheral nervous system (PNS). The location of the meninges between the CNS and PNS raises the possibility that the meninges act as guidepost tissue, a source of guidance cues, for developing axons . Here, we investigate the role of meninges in axon guidance by conducting a series of co‐culture in vitro experiments to examine the response of different axonal populations to meninges. Using embryonic mouse neural tissue explants, we provide evidence that motor axons are attracted to spinal cord meninges and sensory axon growth is stimulated upon contact with the meninges. In contrast, commissural axons are repelled by a transient, secreted guidance cue produced by the meninges and results in commissural growth cone collapse. These results demonstrate that the developing meninges produce yet to be identified long‐ and short‐range axon guidance cues that regulate axonal growth in vitro. We show that each axonal population responds to meninges in a manner consistent with their in vivo trajectories relative to the meninges, suggesting that the observed meningeal guidance factors contribute to proper nervous system wiring.