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WIREs Dev Biol
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Vertebrate spinal commissural neurons: a model system for studying axon guidance beyond the midline

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Abstract For bilaterally symmetric organisms, the transfer of information between the left and right side of the nervous system is mediated by commissures formed by neurons that project their axons across the body midline to the contralateral side of the central nervous system (CNS). After crossing the midline, many of these axons must travel long distances to reach their targets, including those that extend from spinal commissural neurons. Owing to the highly stereotyped trajectories of spinal commissural neurons that can be divided into several segments as these axons project to their targets, it is an ideal system for investigators to ask fundamental questions related to mechanisms of short‐ and long‐range axon guidance, fasciculation, and choice point decisions at the midline intermediate target. In addition, studies of patterning genes of the nervous system have revealed complex transcription factor codes that function in a combinatorial fashion to specify individual classes of spinal neurons including commissural neurons. Despite these advances and the functional importance of spinal commissural neurons in mediating the transfer of external sensory information from the peripheral nervous system (PNS) to the CNS, only a handful of studies have begun to elucidate the mechanistic logic underlying their long‐range pathfinding and the characterization of their synaptic targets. Using in vitro assays, in vivo labeling methodologies, in combination with both loss‐ and gain‐of‐function experiments, several studies have revealed that the molecular mechanisms of long‐range spinal commissural axon pathfinding involve an interplay between classical axon guidance cues, morphogens and cell adhesion molecules. WIREs Dev Biol 2015, 4:283–297. doi: 10.1002/wdev.173 This article is categorized under: Establishment of Spatial and Temporal Patterns > Gradients Nervous System Development > Vertebrates: General Principles Nervous System Development > Vertebrates: Regional Development
Diversity of spinal commissural neurons. (a) Schematic of a transverse spinal cord section showing distinct dorsal and ventral populations of spinal interneurons. Chemorepellent and chemoattractant gradients located in the dorsal and ventral spinal cord, respectively, direct commissural axons towards the ventral spinal cord. Subpopulations of commissural neurons originate along the dorsoventral extent within distinct lamina of the spinal cord. (b) Once commissural axons have crossed the midline, they are guided along the anterior–posterior axis by opposing gradients of attractive and repulsive cues. Post‐crossing commissural axons project within the ventral marginal zone next to the floor plate or within the lateral marginal zone. (c) Schematic diagram of an open book preparation illustrating the diversity of post‐crossing axon trajectories. Commissural neurons with synaptic targets within the cerebellum (Cb) or midbrain (Mb) have axonal trajectories next to the midline in the MLC forming the ventral funiculus (VF) or along a more intermediate lateral path within the ILC, forming the lateral funiculus (LF). Commissural neurons terminating locally within the spinal cord inter‐segments form ascending (aCIN), descending (dCIN), or bilateral (adCIN) contralateral projections. A subset of ventral GABAergic commissural neurons projects to midbrain targets along the MLC trajectory.
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Heterogeneous population of spinal commissural neurons. (a) Diagram showing the use of the lipid soluble cell membrane tracer, 1,1′‐dioctadecyl‐3,3,3′,3′ tetramethylindocarbocyanine perchlorate (DiI). DiI was applied in the ventral commissure (VC) for retrograde tracing to locate the cell bodies of commissural neurons on the ipsilateral side. (b) Image depicts drawings of commissural neurons identified based on their dendritic profile and cell body locations along the dorsoventral axis of the E17.5 transverse spinal cord. Similarly shaped neurons tend to cluster in the same area. DiI was positioned at several sites within the spinal cord including the ventral commissure (VC), lateral funiculus (LF), and the ventral funiculus (VF) on the contralateral side. Injection sites are indicated by the red triangles.
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Neuropilin‐2 guides ATOH1 post‐crossing axons. Open‐book spinal cord schematic displaying the role of NRP2 in the guidance of dorsal spinal commissural neurons. Axons examined from Nrp2+/−;Atoh1tauGFP (Control) and Nrp2−/−;Atoh1tauGFP (Mutant) display normal pathfinding for the pre‐crossing segments. Loss of NRP2 results in the misguidance of ATOH1 positive post‐crossing segments. Axons no longer project to the ILC and remain in the MLC. Semaphorins and their receptor molecules function in a recessive manner. Heterozygotes littermates were used as controls since phenotypic analysis revealed no difference when compared to the wild type.
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Summary of post‐crossing spinal commissural axon guidance under the control of SHH and ROBO. (a) Schematic diagrams of open book preparations that summarize experimental results involving 14‐3‐3 proteins. Wild type (green) neurons display mainly two contralateral trajectories, the MLC and ILC. Overexpressing 14‐3‐3 in the commissural neurons (purple) induces a repulsive response to SHH prior to entering the midline. Inhibiting 14‐3‐3 protein function in commissural neurons does not alter pre‐crossing or midline crossing axonal segments, but induced post‐crossing axon defects, including randomized anterior–posterior projections (red). (b) Schematic diagrams of open book preparations summarize experimental results involving SLIT‐ROBO signaling, and N‐cadherin in post‐crossing axonal segments. Wild type (green) neurons display mainly two contralateral trajectories, the MLC and ILC. Overexpressing N‐cadherin prevents the formation of the ILC trajectory (blue). Inhibition of ROBO1/2 (red) prevents the formation of ILC trajectories, but this phenotype is rescued when N‐Cadherin function is also knockdown (purple). FP = floor plate.
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Axon guidance under the control of Semaphorin 6B and Plexin‐A2 in the developing chick. (a) Pre‐crossing commissural axons in the developing chick spinal cord express both the transmembrane SEMA6B and Plexin‐A2 receptor. During this time, SEMA6B and Plexin‐A2 associate through a cis‐interaction, and suggested to inhibit Plexin‐A2 response to secreted class 3 semaphorins. (b) As these axons cross the midline, SEMA6B expressed on the surface of the axons associates with PlexinA2, expressed by the floor plate cells, through a trans‐interaction. This interaction leads to the activation of ‘reverse’ signaling downstream of SEMA6B leading to the guidance of post‐crossing segments of commissural axons. The trans‐interaction is also suggested to allow Plexin‐A2 to become available to respond to class 3 semaphorins. The question marks indicate that the ability of SEMA3s to signal through PlexinA2 is not known.
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ROBO and SHH control of spinal commissural axon guidance. (a) Pre‐crossing axonal segments are attracted ventrally towards the source of Netrin and SHH gradients from the floor plate. Expression of ROBO3.1 within pre‐crossing segments inhibits ROBO1/2 from responding to Slit cues. (b) Upregulation of ROBO3.2 allows ROBO1/2 to become responsive to Slits. (c) Pre‐crossing axons express low levels of 14‐3‐3 proteins. (d) Levels of 14‐3‐3 proteins are upregulated in post‐crossing axonal segments in mouse spinal cords, leading to a decrease in PKA activity. As commissural axons cross the midline, the response to SHH switches from attraction to repulsion. Post‐crossing axons extend anteriorly in response to the high posterior, low anterior SHH gradient.
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