title: Integrins and cAMP mediate netrin-induced growth cone collapse.
abstract: Growth cones integrate a remarkably complex concert of chemical cues to guide axons to their appropriate destinations. Recent work suggests that integrins contribute to axon guidance by interacting with a wide range of extracellular molecules including axon guidance molecules, by mechanisms that are not fully understood. Here, we describe an interaction between integrins and netrin-1 in growth cones that contributes to growth cone collapse. Our data show that netrin-1 causes growth cone collapse in a substratum-specific manner and is integrin-dependent. Netrin-1 causes collapse of cultured chick dorsal root ganglion (DRG) growth cones extending on high levels of laminin-1 (LN) but not growth cones extending on low levels of LN or on fibronectin. Blocking integrin function significantly decreases netrin-induced growth cone collapse on high LN. Netrin-1 and integrins interact on growth cones; netrin-1 causes integrin activation, a conformational shift to a high ligand-affinity state. Netrin-1 directly binds to integrin α3 and α6 peptides, further suggesting a netrin-integrin interaction. Interestingly, our data reveal that netrin-1 increases growth cone levels of cAMP in a substratum-specific manner and that netrin-induced growth cone collapse requires increased cAMP in combination with integrin activation. Manipulations that either decrease cAMP levels or integrin activation block netrin-induced collapse. These results imply a common mechanism for growth cone collapse and novel interactions between integrins, netrin-1 and cAMP that contribute to growth cone guidance.
authors.affiliation: Department of Natural Sciences, Assumption College, Worcester MA 01609, United States; Department of Neurobiology and Anatomy, University of Utah School of Medicine, 401 MREB, 20 North 1900 East, Salt Lake City, UT 84132, United States. Electronic address: mlemons@assumption.edu.
authors.forename: M L
authors.initials: ML
authors.lastname: Lemons
authors.forename: M L
authors.initials: ML
authors.lastname: Abanto
authors.forename: N
authors.initials: N
authors.lastname: Dambrouskas
authors.forename: C C
authors.initials: CC
authors.lastname: Clements
authors.forename: Z
authors.initials: Z
authors.lastname: Deloughery
authors.forename: J
authors.initials: J
authors.lastname: Garozzo
authors.forename: M L
authors.initials: ML
authors.lastname: Condic
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D002478:Cells, Cultured; D002642:Chick Embryo; D002645:Chickens; D000242:Cyclic AMP / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D020439:Growth Cones / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism*; D000075388:Netrin-1; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D005353:Fibronectins; D016023:Integrins; D007797:Laminin; D009414:Nerve Growth Factors; D025521:Tumor Suppressor Proteins; C121346:laminin 1; D000075388:Netrin-1; D000242:Cyclic AMP
keywords: Axon guidance; Cyclic AMP; DRG; FN; Integrin activation; LN; Laminin; Netrin-1; Regeneration; dorsal root ganglion; fibronectin; laminin-1