EphA4 Receptor Shedding Regulates Spinal Motor Axon Guidance

Gatto, Graziana; Morales, Daniel; Kania, Artur; Klein, Rüdiger

doi:10.1016/j.cub.2014.08.028

Cited by 34 publications

(28 citation statements)

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“…One may also get at unresolved questions by creating mutant mice carrying structurally modified molecules. This strategy has been applied to guidance cue receptors to, for example, examine the role of proteolytic processing (Gatto, Morales, Kania, & Klein, ) or of specific membrane domain targeting (Tsui, Gabreski, Hein, & Pierchala, ; see also Morales, ). Producing a mouse expressing a modified, membrane‐bound netrin1, as in the fly mentioned above, would reveal whether all of the cue's activities are, indeed, short‐range.…”

Section: Discussionmentioning

confidence: 99%

A new model for netrin1 in commissural axon guidance

Morales

2017

J of Neuroscience Research

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Now-classic experiments characterized netrin1 as a major player in commissural axon guidance in the spinal cord. The data suggest a chemotactic model in which netrin1 expression in the floor plate forms a concentration gradient that attracts commissural axons. New research published independently in Neuron and in Nature tests this model by deleting netrin1 specifically in the floor plate. Surprisingly, these conditional mutant mice have no overt commissure defects. The authors report that netrin1 decorates the pial surface of the spinal cord and hindbrain, likely deposited by radial processes of progenitor cells in the ventricular zone. They find that deletion of the cue exclusively in the ventricular zone causes commissural axons to take aberrant trajectories, suggesting a short range, haptotactic guidance mechanism as opposed to chemotaxis. This minireview aims to summarize the classic and the new findings and offer some interpretations of the data.

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Section: Discussionmentioning

confidence: 99%

A new model for netrin1 in commissural axon guidance

Morales

2017

J of Neuroscience Research

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“…In drosophila, cleavage of Robo by ADAM10 is required for recruitment of downstream signaling molecules and the axon guidance response (Coleman et al, 2010). Metalloproteases can also decrease the amount of available receptors and/or terminate adhesion and signaling (Bai and Pfaff, 2011; Hinkle et al, 2006; Romi et al, 2014; Hattori et al, 2000; Gatto et al, 2014). …”

Section: Discussionmentioning

confidence: 99%

Genetic specification of left–right asymmetry in the diaphragm muscles and their motor innervation

Charoy

Dinvaut

Chaix

et al. 2017

eLife

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The diaphragm muscle is essential for breathing in mammals. Its asymmetric elevation during contraction correlates with morphological features suggestive of inherent left–right (L/R) asymmetry. Whether this asymmetry is due to L versus R differences in the muscle or in the phrenic nerve activity is unknown. Here, we have combined the analysis of genetically modified mouse models with transcriptomic analysis to show that both the diaphragm muscle and phrenic nerves have asymmetries, which can be established independently of each other during early embryogenesis in pathway instructed by Nodal, a morphogen that also conveys asymmetry in other organs. We further found that phrenic motoneurons receive an early L/R genetic imprint, with L versus R differences both in Slit/Robo signaling and MMP2 activity and in the contribution of both pathways to establish phrenic nerve asymmetry. Our study therefore demonstrates L–R imprinting of spinal motoneurons and describes how L/R modulation of axon guidance signaling helps to match neural circuit formation to organ asymmetry.DOI: http://dx.doi.org/10.7554/eLife.18481.001

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“…Eph receptors signal repulsion in response to their transmembrane ephrin ligands; ephrins can also function as receptors, signaling repulsion in response to Eph binding. Metalloprotease and subsequent γ-secretase cleavage of both Ephs and ephrins have been demonstrated, providing a mechanism through which adhesive interactions can be broken to allow for repulsive signaling (Hattori et al, 2000; Janes et al, 2005; Tomita et al, 2006; Litterst et al, 2007; Lin et al, 2008; Gatto et al, 2014). The importance of this mode of regulation for axon targeting has not yet been established in vivo and a recent study using an EphA4 variant that is insensitive to metalloprotease cleavage suggests that EphA4 proteolysis is not required for EphA4-dependent motor axon targeting (Gatto et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

The Intracellular Domain of the Frazzled/DCC Receptor Is a Transcription Factor Required for Commissural Axon Guidance

Neuhaus-Follini

Bashaw

2015

Neuron

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Summary In commissural neurons of Drosophila, the conserved Frazzled (Fra)/Deleted in Colorectal Cancer (DCC) receptor promotes midline axon crossing by signaling locally in response to Netrin and by inducing transcription of commissureless (comm), an antagonist of Slit-Roundabout midline repulsion, through an unknown mechanism. Here, we show that Fra is cleaved to release its intracellular domain (ICD), which shuttles between the cytoplasm and the nucleus, where it functions as a transcriptional activator. Rescue and gain-of-function experiments demonstrate that the Fra ICD is sufficient to regulate comm expression and that both γ-secretase proteolysis of Fra and Fra's function as a transcriptional activator are required for its ability to regulate comm in vivo. Our data uncover an unexpected role for the Fra ICD as a transcription factor whose activity regulates the responsiveness of commissural axons at the midline and raise the possibility that nuclear signaling may be a common output of axon guidance receptors.

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EphA4 Receptor Shedding Regulates Spinal Motor Axon Guidance

Cited by 34 publications

References 50 publications

A new model for netrin1 in commissural axon guidance

A new model for netrin1 in commissural axon guidance

Genetic specification of left–right asymmetry in the diaphragm muscles and their motor innervation

The Intracellular Domain of the Frazzled/DCC Receptor Is a Transcription Factor Required for Commissural Axon Guidance

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