Presentation/Session Information

Session Information

Session Title: Neuronal Development Session Type: Parallel
Session Location: Grand Horizon Ballroom Session Time: Fri, Jun 26 8:30AM - 11:30AM

Presentation Information

Program Number: 92 Presentation Time: 10:06AM - 10:18AM

Presentation Content

LON-2/Glypican is a modulator of UNC-6/netrin-mediated axon guidance.Cassandra Blanchette, Paola Perrat, Andrea Thackeray, Claire Bénard. Department of Neurobiology, UMass Medical School, Worcester, MA, U

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 provide a missing link in understanding the modulation of UNC-6/netrin signaling in the extracellular milieu. We demonstrate that LON-2/glypican, a heparan sulfate proteoglycan, modulates UNC-6/netrin signaling, and may do this through interactions with the UNC-40/DCC netrin receptor. By combining loss-of-function and gain-of-function approaches, we demonstrate that LON-2/glypican functions in the attractive and repulsive UNC-6/netrin pathways, and guides AVM, the distal tip cells, and the motorneurons. We show that LON-2/glypican functions from the hypodermis, where it is expressed (1), to guide cells and axons. To directly test the associations between LON-2/glypican, UNC-6/netrin, and UNC-40/DCC, we have developed an S2 cell-based assay and demonstrate that LON-2/glypican specifically associates with cells expressing the UNC-40/DCC receptor. The association between LON-2/glypican and UNC-40/DCC-expressing cells occurs via the extracellular portion of UNC-40/DCC, independently of UNC-6/netrin binding. Furthermore, we show that the N-terminal globular region of LON-2/glypican, lacking the three HS chain attachment sites, is functional in UNC-6/netrin-mediated guidance. Our studies unravel a novel mechanism by which LON-2/glypican is produced by substrate hypodermal cells and is released from the membrane to associate with UNC-40/DCC-expressing cells and neurons, enabling the modulation of their responses to UNC-6/netrin during cell and axon migrations. Given the evolutionary conservation of both the UNC-6/netrin pathway components and of glypicans, and that synthesis of HS chains is required for mammalian axons to respond to netrin-1 in vitro (2,3), glypicans are likely to play a role in netrin-mediated axon pathfinding in mammals as well.

1. Gumienny et al., 2007

2. Matsumoto et al., 2007

3. Ogata-Iwao et al., 2011.

Please note: Abstract shown here should NOT be cited in bibliographies. Material contained herein should be treated as personal communication and should be cited as such only with the consent of the author.

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