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  • Review Article
  • Published:

Netrins: beyond the brain

Key Points

  • Although netrins were identified as migrational cues in the developing central nervous system (CNS), recent work has highlighted previously unrecognized functions of netrins beyond the CNS.

  • Processes regulated by netrins outside the CNS include cell adhesion, motility, proliferation, differentiation and, ultimately, cell survival.

  • These netrin-mediated functions have been demonstrated in epithelial tissues, where they regulate normal developmental processes and tumorigenesis, and in endothelial cells, where they contribute to angiogenic processes, both during development and during postnatal life.

  • This article provides a critical analysis of recent work highlighting these previously unrecognized functions of netrins outside the CNS.

  • The primary focus is on the discussion of new work stemming from the demonstration of netrin expression and function in non-neural tissues, as well as the translational implications of these new findings.

Abstract

Named after the Sanskrit word netr, which means 'one who guides', the netrin family of secreted proteins provides migrational cues in the developing central nervous system. Recently, netrins have also been shown to regulate diverse processes (such as cell adhesion, motility, proliferation, differentiation and, ultimately, cell survival) in a number of non-neuronal tissues. In some cases, netrins affect these functions through non-classic netrin receptors, prompting a renewed interest in these factors in and beyond the nervous system.

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Figure 1: Structure and receptors of netrins.
Figure 2: Possible model for the convergence of netrin–DCC and netrin–integrin signalling.
Figure 3: Netrin-1 as a survival cue.
Figure 4: Pancreas morphogenesis.
Figure 5: Lung morphogenesis.
Figure 6: Mammary-gland morphogenesis.
Figure 7: Netrin-1 as a chemorepellent and chemoattractant in angiogenesis.

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Acknowledgements

We are grateful to L. Hinck and L. Crisa for insightful suggestions and comments on the manuscript, and M. Tessier-Lavigne, A. P. Montgomery and A. Hayek for stimulating discussions. Work by V. C. and M. Y. was supported by the National Institutes of Health (NIH) and National Institute of Diabetes and Digestive and Kidney, Juvenile Diabetes Research Foundation and The Larry L. Hillblom Foundation. The National Center for Microscopy and Imaging Research is supported by a P41 NIH grant to M. Ellisman.

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Correspondence to Vincenzo Cirulli.

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FURTHER INFORMATION

Supplementary movies from the study by Lu et al.

The National Center for Microscopy and Imaging Research

The Whittier Institute for Diabetes

University of Califoria, San Diego, Department of Pediatrics

Glossary

Axon

Also know as a nerve fibre. A long, slender projection of a nerve cell. It is the primary vehicle of conduction of electrical impulses away from the neuron's cell body, or soma.

Branching morphogenesis

Development of organ shape by a process of budding and branching from a tubular and/or ductal structure.

Integrins

A large family of α- and β-heterodimeric transmembrane proteins that function as receptors for extracellular matrix components. Some integrin receptors also mediate cell–cell interactions.

Trochlear axons

Axons that arise from nerve cells in the trochlear nucleus in the midbrain to form the fourth cranial nerve.

Lipid raft

A subdomain of the plasma membrane that protrudes from the cell surface and contains a high concentration of cholesterol and sphingolipids.

Notochord

A rod of cells that is located ventrally to the neural tube in early development; it is of central importance to the development of the vertebral column.

Mesenchyme

Also known as embryonic connective tissue. It mainly contains fibroblasts, collagens and other extracellular matrix proteins, and is derived from the mesoderm, the middle layer of the trilaminar germ disc of an embryo.

Commissural axon

An axon that arises in the central nervous system and that crosses the organism's midline.

Endothelial tip cells

Endothelial cells located at the tip of developing blood-vessel stalks during processes of angiogenesis. They are responsible for infiltration and migration through the extracellular environment of developing blood vessels and they contribute to the elongation of angiogenic blood vessels through processes of cell proliferation and assembling of new endothelial cells into growing vessel stalks.

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Cirulli, V., Yebra, M. Netrins: beyond the brain. Nat Rev Mol Cell Biol 8, 296–306 (2007). https://doi.org/10.1038/nrm2142

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