UNC5A promotes neuronal apoptosis during spinal cord development independent of netrin-1

Williams, Megan E.; Lu, Xiaowei; McKenna, William L.; Washington, Raesha; Boyette, Adam H.; Strickland, Phyllis; Dillon, Allison K.; Kaprielian, Zaven; Tessier‐Lavigne, Marc; Hinck, Lindsay

doi:10.1038/nn1736

Cited by 54 publications

(50 citation statements)

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“…In this study it was found that death of embryonic motor neurons in UNC5A (a netrin receptor) Ϫ/Ϫ mice is reduced in vivo (Williams et al, 2006). Although the ligand responsible for the activation of UNC5A is not known, this result is consistent with the possibility that a balance between survival and death signals also determines the number of motor neurons.…”

Section: Semaphorin/plexina3 Signaling Effects On Drg Neuronal Cell Dsupporting

confidence: 73%

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The Semaphorin Receptor PlexinA3 Mediates Neuronal Apoptosis during Dorsal Root Ganglia Development

Ben-Zvi¹,

Manor²,

Schachner³

et al. 2008

J. Neurosci.

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Extensive neuronal cell death during development is believed to be due to a limiting supply of neurotrophic factors. In vitro studies suggest that axon guidance molecules directly regulate neuronal survival, raising the possibility that they play a direct role in neuronal cell death in vivo. However, guidance errors may also influence survival indirectly due to loss of target-derived neurotrophic support. The role of guidance molecules in neuronal death in vivo has thus been difficult to decipher. Semaphorin3A, a repulsive guidance cue for sensory neurons, can induce sensory neuron death in vitro. Null mice studies of the Semaphorin3A coreceptors showed that guidance activity is mediated by PlexinA4, but PlexinA3 partially compensates in PlexinA4 Ϫ/Ϫ mice. Here we demonstrate that both Plexins contribute to Sema3A-induced cell death in vitro, albeit in a different hierarchy. PlexinA3 is absolutely required, while PlexinA4 makes a smaller contribution to cell death. We found that PlexinA3 Ϫ/Ϫ mice, which, unlike PlexinA4 Ϫ/Ϫ mice, do not exhibit sensory axon patterning defects, show reduced neuronal apoptosis and an increased number of DRG neurons. Semaphorin3A involvement in neuronal death in vivo was demonstrated by a sensitization experiment using the proapoptotic effector Bax. Our results identify Plexins as mediators of Semaphorin-induced cell death in vitro, and provide the first evidence implicating Semaphorin/Plexin signaling in neuronal survival independent of its role in axon guidance. The results also support the idea that naturally occurring neuronal cell death reflects not only competition for target-derived trophic factors, but also the action of proapoptotic signaling via a Semaphorin/Plexin pathway.

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Section: Semaphorin/plexina3 Signaling Effects On Drg Neuronal Cell Dsupporting

confidence: 73%

“…Ϫ/Ϫ (Williams et al, 2006) mutants, and may reflect the induction of compensatory nonapoptotic cell death mechanisms. The role of Sema3A as a death inducer in vivo is more complicated to evaluate.…”

Section: Semaphorin/plexina3 Signaling Effects On Drg Neuronal Cell Dmentioning

confidence: 99%

The Semaphorin Receptor PlexinA3 Mediates Neuronal Apoptosis during Dorsal Root Ganglia Development

Ben-Zvi¹,

Manor²,

Schachner³

et al. 2008

J. Neurosci.

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“…Axonal expression of UNC5A by spinal motor neurons on myelin was confirmed immunocytochemically using rabbit polyclonal antibodies against the intracellular domain of UNC5A (Ab 2026, kindly provided by Dr. Hinck, University of California, Santa Cruz, CA). Specificity of antibody 2026 for UNC5A has been well documented previously (Williams et al, 2003(Williams et al, , 2006.…”

Section: Methodsmentioning

confidence: 61%

Netrin-1 Is a Novel Myelin-Associated Inhibitor to Axon Growth

et al. 2008

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We investigated the influence of the bifunctional guidance molecule netrin-1 on axonal growth in the injured adult spinal cord. In the adult, netrin-1 is expressed on mature oligodendrocytes, cells of the central canal, and the meninges. Netrin-1 protein in white matter is selectively enriched adjacent to paranodal loops of myelin in nodes of Ranvier. The repulsion-mediating netrin-1 uncoordinated-5 (UNC5) receptors are expressed by neurons of the corticospinal and rubrospinal projections, and by intrinsic neurons of the spinal cord, both before and after spinal cord injury. Neutralization of netrin-1 in myelin prepared from adult rat spinal cord using UNC5 receptor bodies increases neurite outgrowth from UNC5-expressing spinal motor neurons in vitro. Furthermore, axon regeneration is inhibited in a netrin-1-enriched zone, devoid of other myelin-associated inhibitors, within spinal cord lesion sites in vivo. We conclude that netrin-1 is a novel oligodendrocyte-associated inhibitor that can contribute to axonal growth failure after adult spinal cord injury.

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“…Mice lacking DCC phenocopy the netrin 1 null mice remarkably closely (Fazeli et al, 1997), highlighting the role of DCC as a key netrin 1 receptor. Unc5a null mice are viable and live to adulthood, but exhibit reduced neuronal apoptosis (Williams et al, 2006). Unc5b knockout mice die during embryogenesis due to heart failure and substantial disruption of their vasculature (Lu et al, 2004).…”

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confidence: 99%

Netrins: versatile extracellular cues with diverse functions

2011

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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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UNC5A promotes neuronal apoptosis during spinal cord development independent of netrin-1

Cited by 54 publications

References 14 publications

The Semaphorin Receptor PlexinA3 Mediates Neuronal Apoptosis during Dorsal Root Ganglia Development

The Semaphorin Receptor PlexinA3 Mediates Neuronal Apoptosis during Dorsal Root Ganglia Development

Netrin-1 Is a Novel Myelin-Associated Inhibitor to Axon Growth

Netrins: versatile extracellular cues with diverse functions

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