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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., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The inability of the adult injured mammalian spinal cord to successfully regenerate is not well understood. Studies suggest that both extrinsic and intrinsic factors contribute to regeneration failure. In this review, we focus on intrinsic factors that impact regeneration, in particular integrin receptors and their downstream signaling pathways. We discuss studies that address the impact of integrins and integrin signaling pathways on growth cone guidance and motility and how lessons learned from these studies apply to spinal cord regeneration in vivo.

Cyclic nucleotides regulate the response of both developing and regenerating growth cones to a wide range of guidance molecules through poorly understood mechanisms. It is not clear how cAMP levels are regulated or how they translate into altered growth cone behavior. Here, we show that intracellular cAMP levels are influenced by substrata and integrin receptors. We also show that growth cones require a substratum-specific balance between cAMP levels, integrin function and Rho GTPases to maintain motility and prevent collapse. Embryonic chick dorsal root ganglion neurons plated on different concentrations of laminin extend growth cones at similar speeds, yet have distinct levels of integrin expression, integrin activation and intracellular cAMP levels. Either increasing cAMP signaling or activating integrins enhances the rate of growth cone motility, but only on substrata where these two factors are endogenously low (i.e. low concentrations of laminin). Surprisingly, combining these two positive manipulations induces growth cone collapse and retraction on laminin but not on fibronectin. Collapse and retraction on laminin are Rho and Rac1 GTPase dependent and are associated with internalization of integrins, the primary receptors responsible for adhesion. These observations define a novel pathway through which cAMP influences growth cone motility and establish a link between integrins, cAMP and Rho GTPases in growth cones.