Netrin1 Produced by Neural Progenitors, Not Floor Plate Cells, Is Required for Axon Guidance in the Spinal Cord

Varadarajan, Supraja G.; Kong, Jennifer H.; Phan, Keith D.; Kao, Tzu-Jen; Panaitof, S. Carmen; Cardin, Julie; Eltzschig, Holger K.; Kania, Artur; Novitch, Bennett G.; Butler, Samantha J.

doi:10.1016/j.neuron.2017.03.007

Cited by 164 publications

(225 citation statements)

References 46 publications

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“…Since Netrin-1 is one of major attractive guidance cues produced both by the floor plate (Kennedy et al, 2006; Serafini et al, 1996) and by neural progenitors that constitute the ventral and lateral tissues in the neural tube (Dominici et al, 2017; Varadarajan et al, 2017), we tested if attractive Netrin-1/DCC signals are involved in guiding motor exit points to their proper position.…”

Section: Resultsmentioning

confidence: 99%

“…(Dominici et al, 2017; Hand and Kolodkin, 2017; Varadarajan et al, 2017). However, distinguishing the crucial source of Netrin-1 cue was not possible with the global Netrin-1 mutant that we used in the current study.…”

Section: Discussionmentioning

confidence: 99%

“…The major ventral attractant, Netrin-1, and its receptor DCC, guide axons and several types of neuron migration (Culotti and Merz, 1998; Kawasaki et al, 2006; Serafini et al, 1996; Yee et al, 1999). While Netrin-1 was thought to be derived primarily from the floor plate, and secreted to form a long range ventral-high gradient, recent studies provided evidence that the ventricular zone of spinal cord progenitor cells presents the crucial Netrin-1 cues to promote ventral growth of commissural axons toward the floor plate (Dominici et al, 2017; Varadarajan et al, 2017). …”

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: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

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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“…Other studies have suggested a local, adhesive role for netrin, attaching growth cones to source cells in the developing medulla (Akin and Zipursky, 2016). Moreover, our recent studies in the spinal cord (Varadarajan et al, 2017), with those in the hindbrain (Dominici et al, 2017), have revisited the role of FP-derived netrin1 in axon guidance. In the mouse spinal cord, both neural progenitor cells (NPCs) in the ventricular zone (VZ), and FP cells express netrin1 (Serafini et al, 1996) and netrin1 protein decorates both commissural axons and the pial (basal) margin of the spinal cord (Kennedy et al, 2006; Varadarajan et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Netrin1 establishes multiple boundaries for axon growth in the developing spinal cord

Varadarajan

Butler

2017

Developmental Biology

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The canonical model for netrin1 function proposed that it acted as a long-range chemotropic axon guidance cue. In the developing spinal cord, floor-plate (FP)-derived netrin1 was thought to act as a diffusible attractant to draw commissural axons to the ventral midline. However, our recent studies have shown that netrin1 is dispensable in the FP for axon guidance. We have rather found that netrin1 acts locally: netrin1 is produced by neural progenitor cells (NPCs) in the ventricular zone (VZ), and deposited on the pial surface as a haptotactic adhesive substrate that guides Dcc+ axon growth. Here, we further demonstrate that this netrin1 pial-substrate has an early role orienting pioneering spinal axons, directing them to extend ventrally. However, as development proceeds, commissural axons choose to grow around a boundary of netrin1 expressing cells in VZ, instead of continuing to extend alongside the netrin1 pial-substrate in the ventral spinal cord. This observation suggests netrin1 may supply a more complex activity than pure adhesion, with netrin1-expressing cells also supplying a growth boundary for axons. Supporting this possibility, we have observed that additional domains of netrin1 expression arise adjacent to the dorsal root entry zone (DREZ) in E12.5 mice that are also required to sculpt axonal growth. Together, our studies suggest that netrin1 provides “hederal” boundaries: a local growth substrate that promotes axon extension, while also preventing local innervation of netrin1-expressing domains.

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“…Netrin-1 is expressed at the midline of the developing CNS and acts as an attractive or repulsive cue for different populations of crossing/commissural axons (2). The classical view that attraction of commissural axons is mediated by a gradient of floor-plate-derived netrin-1 has been recently challenged: netrin-1 primarily acts locally by promoting growth cone adhesion (3,4). In netrin-1-KO mice, many commissural axons fail to cross the midline in the corpus callosum, the hippocampal and anterior commissures, the corticospinal tract (CST), and the spinal cord (5-7).…”

Section: Introductionmentioning

confidence: 99%

Mutations in the netrin-1 gene cause congenital mirror movements

Méneret¹,

Franz²,

Trouillard³

et al. 2017

Journal of Clinical Investigation

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Netrin1 Produced by Neural Progenitors, Not Floor Plate Cells, Is Required for Axon Guidance in the Spinal Cord

Cited by 164 publications

References 46 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

Netrin1 establishes multiple boundaries for axon growth in the developing spinal cord

Mutations in the netrin-1 gene cause congenital mirror movements

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