Netrins are a family of secreted proteins that function as chemotropic guidance cues, directing cell and axon migration during neural development. By directing cell migration and mediating cell–cell adhesion, netrins also influence the morphogenesis of lung, pancreas, mammary gland and vasculature. Netrin receptors include the transmembrane proteins ‘deleted in colorectal cancer’ (DCC), its relative neogenin, and members of the UNC5 family.

Keywords: axon guidance; cell migration; DCC; UNC5; tissue morphogenesis

Figure 1.

Netrins guide axon and cell migration, and direct tissue morphogenesis (a) Netrin‐1 secreted by the floor plate (FP) attracts and repels axons from the ventral midline; (b) Embryonic spinal commissural axon outgrowth assay: an explant of dorsal embryonic rat spinal cord containing the commissural neuron cell bodies is embedded in a collagen gel. In the absence of a source of netrin‐1, such as the FP, the extending axons remain within the explant. In the presence of netrin‐1, the axons emerge from the explant and grow into the collagen; (c) Embryonic spinal commissural axon turning assay: a segment of embryonic day 11 rat spinal cord is embedded into a 3‐D collagen gel and an explant of the FP is grafted on to one end. Neurons within ∼250 μm of the ectopic FP turn away from their normal dorsal to ventral trajectory and grow towards the grafted FP; (d) Pipette turning assay: a gradient of netrin‐1 (blue) puffed from a pipette acts as a chemoattractant for some axons (green) and a repellent for others (red); (e) In the mature mammalian CNS, netrin‐1 is localized to periaxonal myelin suggesting a role regulating interactions between axonal and oligodendroglial membranes; (f) Netrin released by epithelial stalk cells inhibits proximal branch formation during lung morphogenesis; (g) In the developing mammary gland, netrin released by luminal cells is essential for appropriate adhesive interactions between luminal and cap cells; (h) Netrin secreted by somites regulates branching of endothelial tip cells during angiogenesis. Reprinted from Baker KA, Moore SW, Jarjour AA and Kennedy TE (2002) Current Opinion in Neurobiology 16 (5): 529–534 with permission from Elsevier.

Figure 2.

Netrin and netrin receptor structure (a) All netrins contain amino terminal domains V and VI related to corresponding amino terminal domains of laminins. Domain V is composed of cysteine‐rich (EGF) repeats. Domain C in secreted netrins contains many positively charged, basic residues; (b) DCC and UNC5 are receptors for netrin‐1 to ‐3. Ngl1 is a receptor for netrin‐G1; (c) Tree illustrating a phylogenetic relationship based on sequence of the VI and V domains in human netrins and laminins; (d) Phylogenetic tree based on human protein sequences related to the C domain of netrin‐1 (see text for details).

Figure 3.

Netrin signalling (a) Speculative model outlining intracellular events during an attractive response to netrin‐1. In the absence of netrin‐1, the adaptor protein Nck1 and the tyrosine kinase Fak associate with the intracellular domain of DCC. In response to netrin‐1, DCC multimerizes via its P3 domains. Phosphatidylinositol transfer protein‐α (PITPα) associated with the DCC P3 domain has been proposed to promote the generation of phosphoinositides (PIPs) by phosphatidylinositol‐3 kinases (PI3Ks) which are then hydrolysed by phospholipase C (PLC) into IP3 and diacylglycerol (DAG) leading to calcium release from intracellular stores and activation of protein kinase C (PKC). Netrin‐1 induced phosphorylation of the intracellular domain of DCC and associated proteins such as Fak, leads to recruitment and activation of the tyrosine kinase fyn and the serine/threonine kinase Pak. Subsequent activation of ρ GTPase guanine exchange factors leads to the activation of Cdc42 and Rac, causing remodelling of the cytoskeleton through proteins such as N‐WASP, Ena/Vasp and Map1b; (b) Speculative model outlining the intracellular events occurring during short‐ and long‐range repulsion to netrin‐1. In the absence of netrin‐1, Mena and ankyrin link UNC5 to the cytoskeleton. Upon binding netrin‐1, UNC5 is tyrosine phosphorylated, independently of DCC, by tyrosine kinases such as Src1. Netrin‐1 induces recruitment of the tyrosine phosphatase Shp2 to a phosphorylated tyrosine residue in the ZU5 domain. PIPs have been proposed to regulate interaction of Max‐1 with UNC5. Long‐range repulsion to netrin‐1 requires association between the intracellular domains of UNC5 and DCC.



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Further Reading

Barallobre MJ, Pascual M, Del Rio JA and Soriano E (2005) The netrin family of guidance factors: emphasis on netrin‐1 signalling. Brain Research. Brain Research Reviews 49: 22–47.

Dickson BJ (2002) Molecular mechanisms of axon guidance. Science 298: 1959–1964.

Huber AB, Kolodkin AL, Ginty DD and Cloutier JF (2003) Signaling at the growth cone: ligand‐receptor complexes and the control of axon growth and guidance. Annual Review of Neuroscience 26: 509–563.

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Moore, Simon W, Tessier‐Lavigne, Marc, and Kennedy, Timothy E(Jul 2007) Netrins. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000830]