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Glypican Is a Modulator of Netrin-Mediated Axon Guidance.

Blanchette CR, Perrat PN, Thackeray A, Bénard CY - PLoS Biol. (2015)

Bottom Line: However, the mechanisms regulating netrin and its receptors in the extracellular milieu are largely unknown.Here we demonstrate that in Caenorhabditis elegans, LON-2/glypican, a heparan sulfate proteoglycan, modulates UNC-6/netrin signaling and may do this through interactions with the UNC-40/DCC receptor.We also find that LON-2/glypican functions from the epidermal substrate cells to guide axons, and we provide evidence that LON-2/glypican associates with UNC-40/DCC receptor-expressing cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.

ABSTRACT
Netrin is a key axon guidance cue that orients axon growth during neural circuit formation. However, the mechanisms regulating netrin and its receptors in the extracellular milieu are largely unknown. Here we demonstrate that in Caenorhabditis elegans, LON-2/glypican, a heparan sulfate proteoglycan, modulates UNC-6/netrin signaling and may do this through interactions with the UNC-40/DCC receptor. We show that developing axons misorient in the absence of LON-2/glypican when the SLT-1/slit guidance pathway is compromised and that LON-2/glypican functions in both the attractive and repulsive UNC-6/netrin pathways. We find that the core LON-2/glypican protein, lacking its heparan sulfate chains, and secreted forms of LON-2/glypican are functional in axon guidance. We also find that LON-2/glypican functions from the epidermal substrate cells to guide axons, and we provide evidence that LON-2/glypican associates with UNC-40/DCC receptor-expressing cells. We propose that LON-2/glypican acts as a modulator of UNC-40/DCC-mediated guidance to fine-tune axonal responses to UNC-6/netrin signals during migration.

No MeSH data available.


Related in: MedlinePlus

A model for the role of LON-2/glypican in UNC-6/netrin-UNC-40/DCC-mediated axon guidance.HSPG LON-2/glypican (red) is expressed from the hyp7 epidermal cells (pink) underlying the migrating growth cone of the AVM neuron (tan). LON-2/glypican is released from the hypodermal cell surface and may associate with the developing axon expressing the receptor UNC-40/DCC (blue), directly or indirectly interacting with UNC-40/DCC, to modulate UNC-6/netrin (green) signaling. A second HSPG, SDN-1/syndecan (black), acts in the SLT-1/Slit-SAX-3/Robo (grey) axon guidance pathway.
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pbio.1002183.g007: A model for the role of LON-2/glypican in UNC-6/netrin-UNC-40/DCC-mediated axon guidance.HSPG LON-2/glypican (red) is expressed from the hyp7 epidermal cells (pink) underlying the migrating growth cone of the AVM neuron (tan). LON-2/glypican is released from the hypodermal cell surface and may associate with the developing axon expressing the receptor UNC-40/DCC (blue), directly or indirectly interacting with UNC-40/DCC, to modulate UNC-6/netrin (green) signaling. A second HSPG, SDN-1/syndecan (black), acts in the SLT-1/Slit-SAX-3/Robo (grey) axon guidance pathway.

Mentions: To provide evidence for the model that LON-2/glypican can function in axon guidance when detached from the plasma membrane, we used a form of LON-2/glypican lacking the GPI anchor, LON-2ΔGPI, which should be directly secreted into the extracellular milieu [31]. LON-2ΔGPI rescued the AVM guidance defects of lon-2 slt-1 double mutants back to the level of slt-1 single mutants (Fig 5C). We also used a truncated form of LON-2/glypican (N-LON-2) containing the N-terminal globular domain, but lacking the C-terminal region, thus removing the three HS attachment sites and the GPI membrane anchor. N-LON-2 also rescued the AVM guidance defects of lon-2 slt-1 double mutants back to the level of slt-1 single mutants (Fig 5C). In contrast, a reciprocal construct containing only the C-terminus with the three HS attachment sites and the GPI anchor (C-LON-2) did not rescue the AVM axon guidance defects of lon-2 slt-1, consistent with the model that the N-terminal globular domain of LON-2/glypican is the key functional domain during guidance (Fig 5C). A secreted form of LON-2/glypican is also functional in DTC guidance, as we found that DTC guidance defects of lon-2/glypican mutants could be rescued by expression of N-LON-2, containing only the N-terminal globular domain (Fig 5D). These findings also support the hypothesis that LON-2/glypican may normally be released from the hypodermis to interact with the unc-6/netrin pathway to direct the migrating growth cone during development (Fig 7).


Glypican Is a Modulator of Netrin-Mediated Axon Guidance.

Blanchette CR, Perrat PN, Thackeray A, Bénard CY - PLoS Biol. (2015)

A model for the role of LON-2/glypican in UNC-6/netrin-UNC-40/DCC-mediated axon guidance.HSPG LON-2/glypican (red) is expressed from the hyp7 epidermal cells (pink) underlying the migrating growth cone of the AVM neuron (tan). LON-2/glypican is released from the hypodermal cell surface and may associate with the developing axon expressing the receptor UNC-40/DCC (blue), directly or indirectly interacting with UNC-40/DCC, to modulate UNC-6/netrin (green) signaling. A second HSPG, SDN-1/syndecan (black), acts in the SLT-1/Slit-SAX-3/Robo (grey) axon guidance pathway.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493048&req=5

pbio.1002183.g007: A model for the role of LON-2/glypican in UNC-6/netrin-UNC-40/DCC-mediated axon guidance.HSPG LON-2/glypican (red) is expressed from the hyp7 epidermal cells (pink) underlying the migrating growth cone of the AVM neuron (tan). LON-2/glypican is released from the hypodermal cell surface and may associate with the developing axon expressing the receptor UNC-40/DCC (blue), directly or indirectly interacting with UNC-40/DCC, to modulate UNC-6/netrin (green) signaling. A second HSPG, SDN-1/syndecan (black), acts in the SLT-1/Slit-SAX-3/Robo (grey) axon guidance pathway.
Mentions: To provide evidence for the model that LON-2/glypican can function in axon guidance when detached from the plasma membrane, we used a form of LON-2/glypican lacking the GPI anchor, LON-2ΔGPI, which should be directly secreted into the extracellular milieu [31]. LON-2ΔGPI rescued the AVM guidance defects of lon-2 slt-1 double mutants back to the level of slt-1 single mutants (Fig 5C). We also used a truncated form of LON-2/glypican (N-LON-2) containing the N-terminal globular domain, but lacking the C-terminal region, thus removing the three HS attachment sites and the GPI membrane anchor. N-LON-2 also rescued the AVM guidance defects of lon-2 slt-1 double mutants back to the level of slt-1 single mutants (Fig 5C). In contrast, a reciprocal construct containing only the C-terminus with the three HS attachment sites and the GPI anchor (C-LON-2) did not rescue the AVM axon guidance defects of lon-2 slt-1, consistent with the model that the N-terminal globular domain of LON-2/glypican is the key functional domain during guidance (Fig 5C). A secreted form of LON-2/glypican is also functional in DTC guidance, as we found that DTC guidance defects of lon-2/glypican mutants could be rescued by expression of N-LON-2, containing only the N-terminal globular domain (Fig 5D). These findings also support the hypothesis that LON-2/glypican may normally be released from the hypodermis to interact with the unc-6/netrin pathway to direct the migrating growth cone during development (Fig 7).

Bottom Line: However, the mechanisms regulating netrin and its receptors in the extracellular milieu are largely unknown.Here we demonstrate that in Caenorhabditis elegans, LON-2/glypican, a heparan sulfate proteoglycan, modulates UNC-6/netrin signaling and may do this through interactions with the UNC-40/DCC receptor.We also find that LON-2/glypican functions from the epidermal substrate cells to guide axons, and we provide evidence that LON-2/glypican associates with UNC-40/DCC receptor-expressing cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.

ABSTRACT
Netrin is a key axon guidance cue that orients axon growth during neural circuit formation. However, the mechanisms regulating netrin and its receptors in the extracellular milieu are largely unknown. Here we demonstrate that in Caenorhabditis elegans, LON-2/glypican, a heparan sulfate proteoglycan, modulates UNC-6/netrin signaling and may do this through interactions with the UNC-40/DCC receptor. We show that developing axons misorient in the absence of LON-2/glypican when the SLT-1/slit guidance pathway is compromised and that LON-2/glypican functions in both the attractive and repulsive UNC-6/netrin pathways. We find that the core LON-2/glypican protein, lacking its heparan sulfate chains, and secreted forms of LON-2/glypican are functional in axon guidance. We also find that LON-2/glypican functions from the epidermal substrate cells to guide axons, and we provide evidence that LON-2/glypican associates with UNC-40/DCC receptor-expressing cells. We propose that LON-2/glypican acts as a modulator of UNC-40/DCC-mediated guidance to fine-tune axonal responses to UNC-6/netrin signals during migration.

No MeSH data available.


Related in: MedlinePlus