Netrins: versatile extracellular cues with diverse functions

Abstract

SummaryNetrins are secreted proteins that were first identified as guidance cues, directing cell and axon migration during neural development. Subsequent findings have demonstrated that netrins can influence the formation of multiple tissues, including the vasculature, lung, pancreas, muscle and mammary gland, by mediating cell migration, cell-cell interactions and cell-extracellular matrix adhesion. Recent evidence also implicates the ongoing expression of netrins and netrin receptors in the maintenance of cell-cell organisation in mature tissues. Here, we review the mechanisms involved in netrin signalling in vertebrate and invertebrate systems and discuss the functions of netrin signalling during the development of neural and non-neural tissues.Key words: DCC, Adhesion, Axon, Neogenin, Netrin, UNC5 IntroductionNetrins are a family of extracellular, laminin-related (see Glossary, Box 1) proteins that function as chemotropic guidance cues for migrating cells and axons during neural development. They act as chemoattractants for some cell types and chemorepellents for others. Loss-of-function mutations in netrin 1 or in certain netrin receptors are lethal in mice, highlighting the importance of netrin signalling during development. Insights into the functions of netrins have arisen from studies across a wide range of animal species, including invertebrates such as the nematode worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster, non-mammalian vertebrates such as the frog Xenopus laevis, and mammals including rats, mice and humans.Since its discovery in the early 1990s, it is now becoming clear that the netrin gene family exhibits a rich biology, with significance beyond neural development, and contributes to the organisation of multiple tissues. Along with a number of other identified axon guidance cues (Hinck, 2004), secreted netrins influence organogenesis outside the central nervous system (CNS), directing cell migration and mediating cell-cell adhesion in the lung, pancreas, mammary gland, vasculature and muscle (Kang et al., 2004; Lejmi et al., 2008;Liu et al., 2004;Lu et al., 2004;Srinivasan et al., 2003;Yebra et al., 2003). Here, we discuss the cell biology of netrin and netrin receptor functions and review the downstream signal transduction mechanisms that they activate. We also provide an overview of netrin function during development, both within the nervous system and within other developing organs and tissues. Netrin family membersThe first reported member of the netrin family, uncoordinated-6 (UNC-6), was identified in a search for gene products that regulate neural development in C. elegans (Ishii et al., 1992). Netrins have since been identified and studied in multiple vertebrate and invertebrate species (Table 1), including X. laevis (de la Torre et al., 1997), D. melanogaster (Harris et al., 1996;Mitchell et al., 1996) and the sea anemone Nematostella vectensis (Matus et al., 2006), an animal that exhibits early hallmarks of the origins of bilateral symmetry. In mammals, three...

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Semaphorin 3A inactivation suppresses ischemia-reperfusion-induced inflammation and acute kidney injury

“…The pathogenesis of AKI is complex and multifactorial in nature. Inflammation, tubular epithelial cell apoptosis, and impaired perfusion are prominent features that promote acute tubular necrosis and subsequent progression to end-stage renal failure (5, 9, 24).Guidance cues represent a class of molecules that play a key role in development by directing cells to reach target tissues or organs through attraction or repulsion (1,8,28). Although these molecules are also expressed in adult tissues, their function in adult organs is poorly understood.…”

“…Guidance cues represent a class of molecules that play a key role in development by directing cells to reach target tissues or organs through attraction or repulsion (1,8,28). Although these molecules are also expressed in adult tissues, their function in adult organs is poorly understood.…”

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