Multiomic Analysis of Neurons with Divergent Projection Patterns Identifies Novel Regulators of Axon Pathfinding
Abstract Axon pathfinding is a key step in neural circuits formation. However, the transcriptional mechanisms regulating its progression remain poorly understood. The binary decision of crossing or avoiding the midline taken by some neuronal axons during development represents a robust model to inve...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-10-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202200615 |
| _version_ | 1798019930910621696 |
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| author | Marta Fernández‐Nogales Maria Teresa López‐Cascales Verónica Murcia‐Belmonte Augusto Escalante Jordi Fernández‐Albert Rafael Muñoz‐Viana Angel Barco Eloísa Herrera |
| author_facet | Marta Fernández‐Nogales Maria Teresa López‐Cascales Verónica Murcia‐Belmonte Augusto Escalante Jordi Fernández‐Albert Rafael Muñoz‐Viana Angel Barco Eloísa Herrera |
| author_sort | Marta Fernández‐Nogales |
| collection | DOAJ |
| description | Abstract Axon pathfinding is a key step in neural circuits formation. However, the transcriptional mechanisms regulating its progression remain poorly understood. The binary decision of crossing or avoiding the midline taken by some neuronal axons during development represents a robust model to investigate the mechanisms that control the selection of axonal trajectories. Here, to identify novel regulators of axon guidance, this work compares the transcriptome and chromatin occupancy profiles of two neuronal subpopulations, ipsilateral (iRGC) and contralateral retinal ganglion cells (cRGC), with similar functions but divergent axon trajectories. These analyses retrieved a number of genes encoding for proteins not previously implicated in axon pathfinding. In vivo functional experiments confirm the implication of some of these candidates in axonal navigation. Among the candidate genes, γ‐synuclein is identified as essential for inducing midline crossing. Footprint and luciferase assays demonstrate that this small‐sized protein is regulated by the transcription factor (TF) Pou4f1 in cRGCs. It is also shown that Lhx2/9 are specifically expressed in iRGCs and control a program that partially overlaps with that regulated by Zic2, previously described as essential for iRGC specification. Overall, the analyses identify dozens of new molecules potentially involved in axon guidance and reveal the regulatory logic behind the selection of axonal trajectories. |
| first_indexed | 2024-04-11T16:49:24Z |
| format | Article |
| id | doaj.art-e5963499a88a4fdba696ca211529d8ca |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-11T16:49:24Z |
| publishDate | 2022-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-e5963499a88a4fdba696ca211529d8ca2022-12-22T04:13:30ZengWileyAdvanced Science2198-38442022-10-01929n/an/a10.1002/advs.202200615Multiomic Analysis of Neurons with Divergent Projection Patterns Identifies Novel Regulators of Axon PathfindingMarta Fernández‐Nogales0Maria Teresa López‐Cascales1Verónica Murcia‐Belmonte2Augusto Escalante3Jordi Fernández‐Albert4Rafael Muñoz‐Viana5Angel Barco6Eloísa Herrera7Instituto de Neurociencias (Consejo Superior de Investigaciones Científicas ‐Universidad Miguel Hernández de Elche, CSIC‐UMH) San Juan de Alicante Av. Santiago Ramón y Cajal s/n Alicante 03550 SpainInstituto de Neurociencias (Consejo Superior de Investigaciones Científicas ‐Universidad Miguel Hernández de Elche, CSIC‐UMH) San Juan de Alicante Av. Santiago Ramón y Cajal s/n Alicante 03550 SpainInstituto de Neurociencias (Consejo Superior de Investigaciones Científicas ‐Universidad Miguel Hernández de Elche, CSIC‐UMH) San Juan de Alicante Av. Santiago Ramón y Cajal s/n Alicante 03550 SpainInstituto de Neurociencias (Consejo Superior de Investigaciones Científicas ‐Universidad Miguel Hernández de Elche, CSIC‐UMH) San Juan de Alicante Av. Santiago Ramón y Cajal s/n Alicante 03550 SpainInstituto de Neurociencias (Consejo Superior de Investigaciones Científicas ‐Universidad Miguel Hernández de Elche, CSIC‐UMH) San Juan de Alicante Av. Santiago Ramón y Cajal s/n Alicante 03550 SpainInstituto de Neurociencias (Consejo Superior de Investigaciones Científicas ‐Universidad Miguel Hernández de Elche, CSIC‐UMH) San Juan de Alicante Av. Santiago Ramón y Cajal s/n Alicante 03550 SpainInstituto de Neurociencias (Consejo Superior de Investigaciones Científicas ‐Universidad Miguel Hernández de Elche, CSIC‐UMH) San Juan de Alicante Av. Santiago Ramón y Cajal s/n Alicante 03550 SpainInstituto de Neurociencias (Consejo Superior de Investigaciones Científicas ‐Universidad Miguel Hernández de Elche, CSIC‐UMH) San Juan de Alicante Av. Santiago Ramón y Cajal s/n Alicante 03550 SpainAbstract Axon pathfinding is a key step in neural circuits formation. However, the transcriptional mechanisms regulating its progression remain poorly understood. The binary decision of crossing or avoiding the midline taken by some neuronal axons during development represents a robust model to investigate the mechanisms that control the selection of axonal trajectories. Here, to identify novel regulators of axon guidance, this work compares the transcriptome and chromatin occupancy profiles of two neuronal subpopulations, ipsilateral (iRGC) and contralateral retinal ganglion cells (cRGC), with similar functions but divergent axon trajectories. These analyses retrieved a number of genes encoding for proteins not previously implicated in axon pathfinding. In vivo functional experiments confirm the implication of some of these candidates in axonal navigation. Among the candidate genes, γ‐synuclein is identified as essential for inducing midline crossing. Footprint and luciferase assays demonstrate that this small‐sized protein is regulated by the transcription factor (TF) Pou4f1 in cRGCs. It is also shown that Lhx2/9 are specifically expressed in iRGCs and control a program that partially overlaps with that regulated by Zic2, previously described as essential for iRGC specification. Overall, the analyses identify dozens of new molecules potentially involved in axon guidance and reveal the regulatory logic behind the selection of axonal trajectories.https://doi.org/10.1002/advs.202200615axon guidanceaxon midline decisionschromatin bindingintegrinsLhxNrp2 |
| spellingShingle | Marta Fernández‐Nogales Maria Teresa López‐Cascales Verónica Murcia‐Belmonte Augusto Escalante Jordi Fernández‐Albert Rafael Muñoz‐Viana Angel Barco Eloísa Herrera Multiomic Analysis of Neurons with Divergent Projection Patterns Identifies Novel Regulators of Axon Pathfinding Advanced Science axon guidance axon midline decisions chromatin binding integrins Lhx Nrp2 |
| title | Multiomic Analysis of Neurons with Divergent Projection Patterns Identifies Novel Regulators of Axon Pathfinding |
| title_full | Multiomic Analysis of Neurons with Divergent Projection Patterns Identifies Novel Regulators of Axon Pathfinding |
| title_fullStr | Multiomic Analysis of Neurons with Divergent Projection Patterns Identifies Novel Regulators of Axon Pathfinding |
| title_full_unstemmed | Multiomic Analysis of Neurons with Divergent Projection Patterns Identifies Novel Regulators of Axon Pathfinding |
| title_short | Multiomic Analysis of Neurons with Divergent Projection Patterns Identifies Novel Regulators of Axon Pathfinding |
| title_sort | multiomic analysis of neurons with divergent projection patterns identifies novel regulators of axon pathfinding |
| topic | axon guidance axon midline decisions chromatin binding integrins Lhx Nrp2 |
| url | https://doi.org/10.1002/advs.202200615 |
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