Netrin Signaling
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Netrin Signaling
Directional information is provided to migrating neurons and growth cones in the form of extracellular cues, whose presence, absence, or concentration differential is transduced into effects on the cytoskeletal machinery that underlie motility. Among the best-characterized secreted guidance cues are the Netrins, Semaphorins, Ephrins, and Slit protein families. Several of these factors are bifunctional, producing positive growth and guidance effects on some growth cone populations and negative effects on others (Ref.1).

Netrins comprise a phylogenetically conserved family of guidance cues related to the extracellular matrix molecule laminin. Netrins are secreted from the floor plate and ventral spinal cord and act as a chemoattractant for commissural axons. They are bifunctional and attract some axons and repel others. Netrin-induced attraction is mediated by the DCC (Deleted in Colorectal Cancer) family of receptors that include Frazzled in Drosophila, UNC40 and UNC5 in C. elegans, and their respective mammalian homologues DCC, Neogenin and UNC5H-1, -2, -3 and -4. The intracellular domain of DCC has several motifs (P1, P2 and P3) that are conserved among C. elegans, Drosophila and mammals. Netrin engagement causes multimerization of DCC receptors, mediated by the association of P3 regions, and leads to attraction and stimulation of axonal growth (Ref.3). The intracellular domain of UNC5 consists of several recognizable domains, including a death domain, which is found in many apoptosis regulating proteins and is likely to be involved in protein-protein interaction; a ZU5 domain, which is also present in the GAP junction protein ZO1, and a DB (DCC-Binding) domain, which has an important role in mediating its interaction with DCC. DCC is required for both the attractive and repulsive responses, whereas UNC5 is required only for the repulsion of some axons. Activation of DCC and DCC-UNC5 by Netrin1 triggers two different cyclic nucleotide signaling pathways. Activation of DCC leads to activation of CaCnLs (L-Type Ca2+ Channels). In the absence of UNC5, DCC activation also triggers a cAMP (cyclic Adenosine 3, 5’-Monophosphate)-dependent signaling pathway and enhances CaCnL activity. Enhanced Ca2+ entry, together with additional Ca2+ release from RyRs (Ryanodine Receptor Channels) and IP3 (Inositol 1,4,5-trisphosphate Receptors) in the endoplasmic reticulum (Ref.2), creates a high-level gradient of [Ca2+]i (intracellular Ca2+ concentration) favoring growth-cone attraction. In the presence of UNC5, Netrin1 activation of DCC-UNC5 also triggers cGMP (cyclic Guanosine Monophosphate) signaling, mediated by Arachidonic Acid pathway, which in turn elevates 12-HPETE (12-Hydroperoxy-5, 8, 10, 14-Eicosatetraenoic Acid) and PGK (Protein Kinase, cGMP-dependent Type-I). This results in decreased Ca2+ currents and growth-cone repulsion. Thus, different spatial patterns of [Ca2+]i at the growth cone are responsible for activating different sets of downstream effectors resulting in bi-directional turning responses. In vertebrates, netrin attraction also involves PLC (Phospholipase-C), PI3K (Phosphatidylinositol 3-Kinase), MAPK (Mitogen-Activated Protein Kinases), PKA (Protein Kinase-A) and the small GTPases CDC42 and Rac. Inhibition of PLC and PI3K reduces axon attraction by Netrin. The MAPK have been implicated in adaptation of axonal responses to netrin. The proline-rich motif in DCC bind to the SH3 domain of Nck1, an adaptor protein with both SH2 and SH3 domains that mediate Rac activation by DCC (Ref.2). Rac activates a putative actin-binding protein Ablim whereas DCC also activates Drosophila Ena (Enabled) and mammalian homologues EnaH, VASP (Vasodilator-Stimulated Phosphoprotein) and EVL (EnaH/ Vasp-like).

Netrin has recently been found to increase local protein synthesis and degradation in the growth cones of retinal axons, and this netrin-induced protein synthesis seems to be required for both attraction and repulsion. In addition to their roles in axon guidance, netrins also influence the peripheral projections of motor axons to their target muscles. Caln (Calcineurin) and NFAT(Nuclear Factor of Activated T-Cell) have recently been found to act downstream of the DCC receptor to promote axon outgrowth (Ref.4).