Cell migration and axon guidance at the border between central and peripheral nervous system

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Science  30 Aug 2019:
Vol. 365, Issue 6456, eaaw8231
DOI: 10.1126/science.aaw8231

Neurons negotiating boundaries

Barriers around the brain and spinal cord separate central from peripheral nervous systems, yet the two systems are interlinked. Suter and Jaworski review what is known about how cells, axons, and signals negotiate the boundary zone. Understanding what goes wrong in boundary transgressions reveals the inner workings of multiple, partially redundant mechanisms built during development that separate the two compartments in adulthood.

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Structured Abstract


In vertebrates, the central and peripheral nervous system (CNS and PNS, respectively) are segregated at the cellular level. The CNS encompasses the brain and spinal cord, and the PNS is composed of numerous ganglia and nerves in the body periphery. Each subsystem is characterized by specialized neurons and unique glial cell types critical for neural circuit function. During development, virtually all CNS neurons and glia arise from progenitors located within this subdivision of the nervous system, and the vast majority of PNS-resident cells originate from the neural crest and ectodermal placodes in the periphery. However, it has become evident that at least a subset of peripheral glia is generated in the CNS and migrates into the PNS. Further, whereas most CNS and PNS neurons project axons exclusively within the same subdivision that houses their cell body, hindbrain and spinal cord motor neurons innervate various peripheral targets, and peripheral sensory neurons send axons into the CNS. Therefore, during development, when neurons and glia migrate to their destinations and axons navigate to their targets, the CNS-PNS interface must be permeable to select cells and axons at specific locations but prevent intermixing of most other CNS and PNS components. The cellular and molecular mechanisms that establish this pattern of segregation and selective connectivity are now beginning to be understood.


Multiple cell types and signaling pathways exert tight control over the movement of cells and axons between the developing vertebrate CNS and PNS. A multilayered barrier surrounds most of the brain and spinal cord to prevent aberrant spillover of CNS and PNS components, but specialized access points called transition zones allow regulated cell migration and axon growth across the CNS-PNS boundary. Studies in various vertebrate species have begun to unravel some of the rules that govern cellular traffic at the CNS-PNS interface. It has become apparent that inhibitory signals from specialized cells located at the CNS-PNS border help to confine migrating cells and nascent axons to one nervous system subdivision; the cues that attract cells and axons to their correct targets are also important for preventing aberrant crossing of the CNS-PNS border. When these signaling pathways are disrupted, transition zones are particularly vulnerable to transgressions by cells and axons that would normally remain within their nervous system compartment. The permissive nature of transition zones is further underscored by the fact that cells in the mature nervous system can occasionally traverse these windows in response to injury. The developmental mechanisms that direct the correct cells and axons toward and across transition zones are still poorly understood, but attractive signals from cells at or beyond the CNS-PNS interface appear to play important roles. Furthermore, axons that need to cross the border are guided there by cues that repel them from inappropriate targets within their nervous system subdivision of origin, and they actively filter out guidance information that would otherwise steer them away from transition zones. Beyond this selective responsiveness to directional signals, these axons also use specialized subcellular structures to penetrate CNS-PNS barrier constituents.


The tight regulation of cell migration and axon navigation at the developing CNS-PNS interface is critical for establishing proper neuronal connectivity and allocating functionally specialized cells to the two major nervous system subdivisions. Further investigation of the relevant mechanisms holds the promise to elucidate the full repertoire of cellular interactions, guidance molecules, and signal transduction pathways that control this key dividing line in the nervous system. Because the fundamental division of the nervous system into central and peripheral compartments appears conserved across species, including some invertebrates, continuing to study the CNS-PNS boundary in multiple model organisms will contribute to understanding the evolution of nervous system organizing principles. Moreover, insights into signaling mechanisms at the CNS-PNS interface could aid in the development of therapeutic approaches that rekindle developmental plasticity at transition zones in the mature nervous system and promote regeneration after injury or onset of neurodegenerative disease.

Control of the CNS-PNS boundary.

During nervous system development, most glia, neurons, and axons are prevented from crossing the CNS-PNS border, whereas select subsets are allowed to move between the two compartments. Physical barriers and combinations of attractive and repulsive cues control cell behaviors at the CNS-PNS dividing line.


The central and peripheral nervous system (CNS and PNS, respectively) are composed of distinct neuronal and glial cell types with specialized functional properties. However, a small number of select cells traverse the CNS-PNS boundary and connect these two major subdivisions of the nervous system. This pattern of segregation and selective connectivity is established during embryonic development, when neurons and glia migrate to their destinations and axons project to their targets. Here, we provide an overview of the cellular and molecular mechanisms that control cell migration and axon guidance at the vertebrate CNS-PNS border. We highlight recent advances on how cell bodies and axons are instructed to either cross or respect this boundary, and present open questions concerning the development and plasticity of the CNS-PNS interface.

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