Pioneer midbrain longitudinal axons navigate using a balance of Netrin attraction and Slit repulsion

Kim, Min Kyung; Farmer, W. Todd; Bjorke, Brielle; McMahon, Samuel A; Fabre, Pierre J.; Charron, Frédéric; Mastick, Grant S.

doi:10.1186/1749-8104-9-17

Cited by 26 publications

(30 citation statements)

References 67 publications

(92 reference statements)

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“…As combined Netrin-1 and Robo mutations caused a lethal genetic interaction, we obtained only one Netrin-1/Robo1/2 triple homozygous mutant embryos even though they are predicted at 1/16 ratios, which we previously reported (Kim et al, 2014). The triple mutant had the Netrin-1 − and β-galactosidase + floor plate (Fig.…”

Section: Methodsmentioning

confidence: 54%

“…To assay axon outgrowth, explants were cultured with or without Netrin-1 (200 ng/ml) for 48 hours. To assay directional effects, localized Netrin-1 sources were provided as described in our previous paper (Kim et al, 2014). Explants are co-cultured with aggregates of COS-7 cells transfected with no plasmid (mock) or Netrin-1 expression plasmid (gift of Marc Tessier-Lavigne, Rockefeller) for 48 hours.…”

Section: Methodsmentioning

confidence: 99%

“…The floor plate and nearby tissues produce several types of guidance cues with well-known roles in guiding developing axons (Colamarino and Tessier-Lavigne, 1995b; Stein and Tessier-Lavigne, 2001). Commissural and longitudinal axons navigate through the neural tube responding to these secreted signals (Farmer et al, 2008; Kim et al, 2014; Serafini et al, 1996; Shoja-Taheri et al, 2015; Ypsilanti et al, 2010). The secreted Slit proteins are major repellents produced by the ventral midline and are expressed along the anteroposterior axis (Brose et al, 1999; Rothberg et al, 1990), and the Slit receptors Robo1 and Robo2 are expressed by motor neurons (Brose et al, 1999; Hammond et al, 2005; Kim et al, 2015; Lee et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Motor axons are guided to exit points in the spinal cord by Slit and Netrin signals

Kim

Fontelonga

Lee

et al. 2017

Developmental Biology

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In the spinal cord, motor axons project out the neural tube at specific exit points, then bundle together to project toward target muscles. The molecular signals that guide motor axons to and out of their exit points remain undefined. Since motor axons and their exit points are located near the floor plate, guidance signals produced by the floor plate and adjacent ventral tissues could influence motor axons as they project toward and out of exit points. The secreted Slit proteins are major floor plate repellents, and motor neurons express two Slit receptors, Robo1 and Robo2. Using mutant mouse embryos at early stages of motor axon exit, we found that motor exit points shifted ventrally in Robo1/2 or Slit1/2 double mutants. Along with the ventral shift, mutant axons had abnormal trajectories both within the neural tube toward the exit point, and after exit into the periphery. In contrast, the absence of the major ventral attractant, Netrin-1, or its receptor, DCC caused motor exit points to shift dorsally. Netrin-1 attraction on spinal motor axons was demonstrated by in vitro explant assays, showing that Netrin-1 increased outgrowth and attracted cultured spinal motor axons. The opposing effects of Slit/Robo and Netrin-1/DCC signals were tested genetically by combining Netrin-1 and Robo1/2 mutations. The location of exit points in the combined mutants was significantly recovered to their normal position compared to Netrin-1 or Robo1/2 mutants. Together, these results suggest that the proper position of motor exit points is determined by a “push-pull” mechanism, pulled ventrally by Netrin-1/DCC attraction and pushed dorsally by Slit/Robo repulsion.

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Section: Methodsmentioning

confidence: 54%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Motor axons are guided to exit points in the spinal cord by Slit and Netrin signals

Kim

Fontelonga

Lee

et al. 2017

Developmental Biology

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“…An example that may be more similar to the mechanism that we have uncovered for motor neurons is the parallel independent Netrin and Slit guidance of fly commissural axons (Garbe and Bashaw, 2007). In another recent study, we have shown that simultaneous Netrin-1/DCC and Slit/Robo signals guide pioneer longitudinal axons through the mouse hindbrain, providing further evidence of neurons that balance Netrin1 attraction and Slit repulsion (Kim et al, 2014). …”

Section: Discussionmentioning

confidence: 65%

Motor neuron cell bodies are actively positioned by Slit/Robo repulsion and Netrin/DCC attraction

Kim

Fontelonga

Roesener

et al. 2015

Developmental Biology

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Motor neurons differentiate from a ventral column of progenitors and settle in static clusters, the motor nuclei, next to the floor plate. Within these cell clusters, motor neurons receive afferent input and project their axons out to muscle targets. The molecular mechanisms that position motor neurons in the neural tube remain poorly understood. The floor plate produces several types of guidance cues with well-known roles in attracting and repelling axons, including the Slit family of chemorepellents via their Robo receptors, and Netrin1 via its DCC attractive receptor. In the present study we found that Islet1+ motor neuron cell bodies invaded the floor plate of Robo1/2 double mutant mouse embryos or Slit 1/2/3 triple mutants. Misplaced neurons were born in their normal progenitor column, but then migrated tangentially into the ventral midline. Robo1 and 2 receptor expression in motor neurons was confirmed by reporter gene staining and anti-Robo antibody labeling. Mis-positioned motor neurons projected their axons longitudinally within the floor plate, and failed to reach their normal exit points. To test for potential counteracting ventral attractive signals, we examined Netrin-1 and DCC mutants, and found that motor neurons shifted dorsally in the hindbrain and spinal cord, suggesting that Netrin-1/DCC signaling normally attracts motor neurons closer to the floor plate. Our results show that motor neurons are actively migrating cells, and are normally trapped in a static position by Slit/Robo repulsion and Netrin-1/DCC attraction.

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“…Finally, we show a genetic interaction between NFM-1 and the secreted guidance cue SLT-1 in AQR migration. In vertebrates, Slit1 and Slit2 are required for guidance of many axons, acting through the Robo family receptors (Nguyen Ba-Charvet et al 1999;Piper et al 2000;Bagri et al 2002;Unni et al 2012;Kim et al 2014). The Slit-Robo guidance pathway is conserved in C. elegans, where SLT-1 acts as a guidance cue for several neurons through SAX-3/Robo (Hao et al 2001;Chang et al 2006;Quinn et al 2006;Xu and Quinn 2012).…”

mentioning

confidence: 99%

The Caenorhabditis elegans NF2/Merlin Molecule NFM-1 Nonautonomously Regulates Neuroblast Migration and Interacts Genetically with the Guidance Cue SLT-1/Slit

Josephson¹,

Aliani²,

Norris³

et al. 2017

Genetics

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During nervous system development, neurons and their progenitors migrate to their final destinations. In Caenorhabditis elegans, the bilateral Q neuroblasts and their descendants migrate long distances in opposite directions, despite being born in the same posterior region. QR on the right migrates anteriorly and generates the AQR neuron positioned near the head, and QL on the left migrates posteriorly, giving rise to the PQR neuron positioned near the tail. In a screen for genes required for AQR and PQR migration, we identified an allele of nfm-1, which encodes a molecule similar to vertebrate NF2/Merlin, an important tumor suppressor in humans. Mutations in NF2 lead to neurofibromatosis type II, characterized by benign tumors of glial tissues. Here we demonstrate that in C. elegans, nfm-1 is required for the ability of Q cells and their descendants to extend protrusions and to migrate, but is not required for direction of migration. Using a combination of mosaic analysis and cell-specific expression, we show that NFM-1 is required nonautonomously, possibly in muscles, to promote Q lineage migrations. We also show a genetic interaction between nfm-1 and the C. elegans Slit homolog slt-1, which encodes a conserved secreted guidance cue. Our results suggest that NFM-1 might be involved in the generation of an extracellular cue that promotes Q neuroblast protrusion and migration that acts with or in parallel to SLT-1. In vertebrates, NF2 and Slit2 interact in axon pathfinding, suggesting a conserved interaction of NF2 and Slit2 in regulating migratory events.

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Pioneer midbrain longitudinal axons navigate using a balance of Netrin attraction and Slit repulsion

Cited by 26 publications

References 67 publications

Motor axons are guided to exit points in the spinal cord by Slit and Netrin signals

Motor axons are guided to exit points in the spinal cord by Slit and Netrin signals

Motor neuron cell bodies are actively positioned by Slit/Robo repulsion and Netrin/DCC attraction

The Caenorhabditis elegans NF2/Merlin Molecule NFM-1 Nonautonomously Regulates Neuroblast Migration and Interacts Genetically with the Guidance Cue SLT-1/Slit

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