Slit-Robo signaling supports motor neuron avoidance of the spinal cord midline through DCC antagonism and other mechanisms
Axon pathfinding and neuronal migration are orchestrated by attractive and repulsive guidance cues. In the mouse spinal cord, repulsion from Slit proteins through Robo family receptors and attraction to Netrin-1, mediated by the receptor DCC, control many aspects of neural circuit formation. This in...
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Frontiers Media S.A.
2025-04-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2025.1563403/full |
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| author | Kelsey R. Nickerson Kelsey R. Nickerson Ferass M. Sammoura Ferass M. Sammoura Yonghong Zhou Yonghong Zhou Alexander Jaworski Alexander Jaworski |
| author_facet | Kelsey R. Nickerson Kelsey R. Nickerson Ferass M. Sammoura Ferass M. Sammoura Yonghong Zhou Yonghong Zhou Alexander Jaworski Alexander Jaworski |
| author_sort | Kelsey R. Nickerson |
| collection | DOAJ |
| description | Axon pathfinding and neuronal migration are orchestrated by attractive and repulsive guidance cues. In the mouse spinal cord, repulsion from Slit proteins through Robo family receptors and attraction to Netrin-1, mediated by the receptor DCC, control many aspects of neural circuit formation. This includes motor neuron wiring, where Robos help prevent both motor neuron cell bodies and axons from aberrantly crossing the spinal cord midline. These functions had been ascribed to Robo signaling being required to counter DCC-mediated attraction to Netrin-1 at the midline, either by mediating repulsion from midline-derived Slits or by silencing DCC signaling. However, the role of DCC in promoting motor neuron and axon midline crossing had not been directly tested. Here, we used in vivo mouse genetics and in vitro axon turning assays to further explore the interplay between Slit and Netrin signaling in motor neuron migration and axon guidance relative to the midline. We find that DCC is a major driver of midline crossing by motor axons, but not motor neuron cell bodies, when Robo1 and Robo2 are knocked out. Further, in vitro results indicate that Netrin-1 attracts motor axons and that Slits can modulate the chemotropic response to Netrin-1, converting it from attraction to repulsion. Our findings indicate that Robo signaling allows both motor neuron cell bodies and axons to avoid the midline, but that only motor axons require this pathway to antagonize DCC-dependent midline attraction, which likely involves a combination of mediating Slit repulsion and directly influencing Netrin-DCC signaling output. |
| format | Article |
| id | doaj-art-dfa28b0c008c43ee9a52791533ffd9ff |
| institution | OA Journals |
| issn | 2296-634X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj-art-dfa28b0c008c43ee9a52791533ffd9ff2025-08-20T02:16:50ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2025-04-011310.3389/fcell.2025.15634031563403Slit-Robo signaling supports motor neuron avoidance of the spinal cord midline through DCC antagonism and other mechanismsKelsey R. Nickerson0Kelsey R. Nickerson1Ferass M. Sammoura2Ferass M. Sammoura3Yonghong Zhou4Yonghong Zhou5Alexander Jaworski6Alexander Jaworski7Department of Neuroscience, Brown University, Providence, RI, United StatesRobert J. and Nancy D. Carney Institute for Brain Science, Brown University, Providence, RI, United StatesDepartment of Neuroscience, Brown University, Providence, RI, United StatesRobert J. and Nancy D. Carney Institute for Brain Science, Brown University, Providence, RI, United StatesDepartment of Neuroscience, Brown University, Providence, RI, United StatesRobert J. and Nancy D. Carney Institute for Brain Science, Brown University, Providence, RI, United StatesDepartment of Neuroscience, Brown University, Providence, RI, United StatesRobert J. and Nancy D. Carney Institute for Brain Science, Brown University, Providence, RI, United StatesAxon pathfinding and neuronal migration are orchestrated by attractive and repulsive guidance cues. In the mouse spinal cord, repulsion from Slit proteins through Robo family receptors and attraction to Netrin-1, mediated by the receptor DCC, control many aspects of neural circuit formation. This includes motor neuron wiring, where Robos help prevent both motor neuron cell bodies and axons from aberrantly crossing the spinal cord midline. These functions had been ascribed to Robo signaling being required to counter DCC-mediated attraction to Netrin-1 at the midline, either by mediating repulsion from midline-derived Slits or by silencing DCC signaling. However, the role of DCC in promoting motor neuron and axon midline crossing had not been directly tested. Here, we used in vivo mouse genetics and in vitro axon turning assays to further explore the interplay between Slit and Netrin signaling in motor neuron migration and axon guidance relative to the midline. We find that DCC is a major driver of midline crossing by motor axons, but not motor neuron cell bodies, when Robo1 and Robo2 are knocked out. Further, in vitro results indicate that Netrin-1 attracts motor axons and that Slits can modulate the chemotropic response to Netrin-1, converting it from attraction to repulsion. Our findings indicate that Robo signaling allows both motor neuron cell bodies and axons to avoid the midline, but that only motor axons require this pathway to antagonize DCC-dependent midline attraction, which likely involves a combination of mediating Slit repulsion and directly influencing Netrin-DCC signaling output.https://www.frontiersin.org/articles/10.3389/fcell.2025.1563403/fullaxon guidanceneuronal migrationspinal cordmotor neuronrobo signalingcrosstalk |
| spellingShingle | Kelsey R. Nickerson Kelsey R. Nickerson Ferass M. Sammoura Ferass M. Sammoura Yonghong Zhou Yonghong Zhou Alexander Jaworski Alexander Jaworski Slit-Robo signaling supports motor neuron avoidance of the spinal cord midline through DCC antagonism and other mechanisms Frontiers in Cell and Developmental Biology axon guidance neuronal migration spinal cord motor neuron robo signaling crosstalk |
| title | Slit-Robo signaling supports motor neuron avoidance of the spinal cord midline through DCC antagonism and other mechanisms |
| title_full | Slit-Robo signaling supports motor neuron avoidance of the spinal cord midline through DCC antagonism and other mechanisms |
| title_fullStr | Slit-Robo signaling supports motor neuron avoidance of the spinal cord midline through DCC antagonism and other mechanisms |
| title_full_unstemmed | Slit-Robo signaling supports motor neuron avoidance of the spinal cord midline through DCC antagonism and other mechanisms |
| title_short | Slit-Robo signaling supports motor neuron avoidance of the spinal cord midline through DCC antagonism and other mechanisms |
| title_sort | slit robo signaling supports motor neuron avoidance of the spinal cord midline through dcc antagonism and other mechanisms |
| topic | axon guidance neuronal migration spinal cord motor neuron robo signaling crosstalk |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2025.1563403/full |
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