Synergistic integration of Netrin and ephrin axon guidance signals by spinal motor neurons

Poliak, Sebastian; Morales, Daniel; Croteau, Louis-Philippe; Krawchuk, Dayana; Palmesino, Elena; Morton, Susan; Cloutier, Jean-François; Charron, Frédéric; Dalva, Matthew B.; Ackerman, Susan L.; Kao, Tzu-Jen; Kania, Artur

doi:10.7554/elife.10841

Cited by 73 publications

(109 citation statements)

References 77 publications

(128 reference statements)

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“…However while there are trace amounts of netrin1 expression in the netrin1 lacZ/lacZ FP (chevrons, Fig. 2B, H, L) there is no detectable netrin1 transcript in the netrin1 lacZ/lacZ VZ at any stage or any detectable netrin1 protein (Poliak et al, 2015; Varadarajan et al, 2017). …”

Section: Resultsmentioning

confidence: 97%

“…The wall provides a substrate for growth, but is not itself penetrated by the ivy. It remains unresolved how widely hederal boundaries act to establish neural circuits, however further putative examples have been observed in both the central and peripheral nervous systems (Burrill and Easter, 1994; Poliak et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

“…Similar growth-boundaries are likely to direct to axon growth outside of the spinal cord. Motor axons notabl grow alongside netrin1::βgal boundaries as they innervate the limb (Poliak et al, 2015). Netrin1 has also been implicated in the neuronal responses after spinal cord injury (Manitt et al, 2006); a mechanistic understanding of its capacity to direct axon growth is critical if it is to be deployed correctly in therapeutic regenerative contexts.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Varadarajan

Butler

2017

Developmental Biology

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“…EphB2 modulates radial migration, proliferation and cell fate of neural progenitor cell in the subventricular zone (Chumley et al, 2007; Katakowski et al, 2005). Interestingly, Netrin-1 and EphB2 have been shown to work synergistically through the Src family kinase-signaling pathway during neural circuit assembly (Poliak et al, 2015). However, further mechanistic studies will be required to validate the significance and underlying molecular mechanisms by which these putative genes potentially cause viral-mediated microcephaly.…”

Section: Discussionmentioning

confidence: 99%

Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3

et al. 2016

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Emerging evidence from the current outbreak of Zika virus (ZIKV) indicates a strong causal link between Zika and microcephaly. To investigate how ZIKV infection leads to microcephaly, we used human embryonic stem cell-derived cerebral organoids to recapitulate early stage, first trimester fetal brain development. Here we show that a prototype strain of ZIKV MR766 efficiently infects organoids and causes a decrease in overall organoid size that correlates with the kinetics of viral copy number. The innate immune receptor Toll-Like-Receptor 3 (TLR3) was upregulated after ZIKV infection of human organoids and mouse neurospheres and TLR3 inhibition reduced the phenotypic effects of ZIKV infection. Pathway analysis of gene expression changes during TLR3 activation highlighted 41 genes also related to neuronal development, suggesting a mechanistic connection to disrupted neurogenesis. Together, therefore, our findings identify a link between ZIKV-mediated TLR3 activation, perturbed cell fate and a reduction in organoid volume reminiscent of microcephaly.

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“…10E), implicating that another mechanism can act as a backup system if both Slit and Netrin cues are missing. In fact, spinal motor axon navigation is also dependent on other floor plate-derived signals, such as Sema3A and Ephrins (Bai et al, 2011; Poliak et al, 2015), suggesting that the precise motor exit points could be determined by multiple guidance signals. Furthermore, we observed that spinal motor axons still exited out the spinal cord in our Slit/Robo or Netrin-1/DCC mutants.…”

Section: Discussionmentioning

confidence: 99%

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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Synergistic integration of Netrin and ephrin axon guidance signals by spinal motor neurons

Cited by 73 publications

References 77 publications

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

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

Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3

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

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