Three known genes guide circumferential migrations of pioneer axons and mesodermal cells on the nematode body wall. unc-5 affects dorsal migrations, unc-40 primarily affects ventral migrations, and unc-6 affects migrations in both directions. Circumferential movements still occur, but are misdirected, whereas longitudinal movements are normal in these mutants. Pioneer growth cones migrating directly on the epidermis are affected; growth cones migrating along established axon fascicles are normal. Thus these genes affect cell guidance and not cell motility per se. It is proposed that two opposite, adhesive gradients guide circumferential migrations on the epidermis. unc-5, unc-6, and unc-40 may encode these adhesion molecules or their cellular receptors. Neurons have access to the basal lamina and the basolateral surfaces of the epidermis, but mesodermal cells contact only the basal lamina. These genes probably identify molecular cues on the basal lamina that guide mesodermal migrations. The same basal lamina cues, or perhaps related molecules on the epidermal cell surfaces, guide pioneer neurons (Hedgecock, 1990).
Growth cones in developing nervous systems encounter a sequence of extracellular cues during migration. In theory, a growth cone can navigate by selectively expressing or activating surface receptor(s) that recognize extracellular cues appropriate to each migratory phase. Using the simple C. elegans nervous system, attempts were made to demonstrate that path selection by migrating growth cones can be predictably altered by ectopic expression of a single receptor. The unc-5 gene of C. elegans encodes a unique receptor of the immunoglobulin superfamily (UNC-5), required cell-autonomously to guide growth cone and mesodermal cell migrations in a dorsal direction on the epidermis. The UNC-5 receptor induces dorsally oriented axon trajectories when ectopically expressed in the touch receptor neurons, which normally extend pioneer axons longitudinally or ventrally on the epidermis. These errant trajectories depend on unc-6, which encodes a putative epidermal path cue, just as do normal dorsally oriented axon trajectories (such as those of certain motor neurons), suggesting that UNC-5 acts to reorient the touch cell growth cones by using its normal guidance mechanisms. These results support previous evidence that UNC-5 and UNC-6 play instructive rules in guiding growth cone migrations on the epidermis in C. elegans, and indicate that pioneering growth cones, which normally migrate in different directions, may use equivalent intracellular signaling mechanisms for guidance (Hamelin, 1993).
The UNC-5 guidance receptor, in response to the UNC-6/netrin path cue, orients growing axons in a dorsal direction along the epidermis of Caenorhabditis elegans. When ectopically expressed in the touch neurons, which normally extend ventrally or longitudinally, UNC-5 is able to reorient their axons toward the dorsal side in an UNC-6-dependent manner. This forms the basis of a genetic screen to identify other mutations that, like unc-6 mutations, suppress unc-5-induced growth cone guidance. These mutations may identify new components required for pioneer axon guidance by unc-5. This paper describes eight genes that are required for ectopic unc-5-induced growth cone steering. Mutations in four of these identify the previously known axon guidance genes [unc-6 (the ligand for UNC-5), unc-40 (ankyrin repeat proteins serving as a putative link between UNC-5 and the cytoskeleton), unc-34, and unc-44]; mutations in four others identify the novel genes unc-129, seu-1, seu-2, and seu-3. Several of these mutations cause axon guidance defects similar to those found in unc-5 mutants. It is proposed that some or all of these genes may function in a developmentally important unc-5 signaling pathway (Colavita, 1998).
Cell migrations play a critical role in animal development and organogenesis. Here, a mechanism is described by which the migration behaviour of a particular cell type is regulated temporally and coordinated with over-all development of the organism. The hermaphrodite distal tip cells (DTCs) of C. elegans migrate along the body wall in three sequential phases that can be distinguished by the orientation of their movements, which alternate between the anteroposterior and dorsoventral axes. The ventral-to-dorsal second migration phase requires the UNC-6 netrin guidance cue and its receptors UNC-5 and UNC-40, as well as additional UNC-6-independent guidance systems. Evidence is provided that the transcriptional upregulation of unc-5 in the DTCs is coincident with the initiation of the second migration phase, and that premature UNC-5 expression in these cells induces precocious turning in an UNC-6-dependent manner. The DAF-12 steroid hormone receptor, which regulates developmental stage transitions in C. elegans, is required for initiating the first DTC turn and for coincident unc-5 upregulation. Evidence is also presented for the existence of a mechanism that opposes or inhibits UNC-5 function during the longitudinal first migration phase and for a mechanism that facilitates UNC-5 function during turning. The facilitating mechanism presumably does not involve transcriptional regulation of unc-5 but may represent an inhibition of the phase 1 mechanism that opposes or inhibits UNC-5. These results, therefore, reveal the existence of two mechanisms that regulate the UNC-5 receptor and are critical for responsiveness to the UNC-6 netrin guidance cue and for linking the directional guidance of migrating distal tip cells to developmental stage advancements (Su, 2000).
Cell and growth cone migrations along the dorsoventral axis of C. elegans are mediated by the UNC-5 and UNC-40 receptor subtypes for the secreted UNC-6 guidance cue. To characterize UNC-6 receptor function in vivo, genetic interactions were examined between unc-5 and unc-40 in the migrations of the hermaphrodite distal tip cells. Cell migration defects as severe as those associated with a null mutation in unc-6 are produced only by null mutations in both unc-5 and unc-40, indicating that either receptor retains some partial function in the absence of the other. Hypomorphic unc-5 alleles exhibit two distinct types of interallelic genetic interactions. In an unc-40 wild-type genetic background, some pairs of hypomorphic unc-5 alleles exhibit a partial allelic complementation. In an unc-40 null background, however, unc-5 hypomorphs exhibit dominant negative effects. It is proposed that the UNC-5 and UNC-40 netrin receptors can function to mediate chemorepulsion in DTC migrations, either independently or together, and the observed genetic interactions suggest that this flexibility in modes of signaling results from the formation of a variety of oligomeric receptor complexes (Merz, 2001).
Members of the UNC-5 protein family are transmembrane receptors for UNC-6/netrin guidance cues. To analyze the functional roles of different UNC-5 domains, mutations were sequenced in seven severe and three weak alleles of unc-5 in Caenorhabditis elegans. Four severe alleles contain nonsense mutations. Two weak alleles are truncations of the cytodomain, but one is a missense mutation in an extracellular immunoglobulin domain. To survey the function of different regions of UNC-5, wild-type and mutant unc-5::HA transgenes were tested for their ability to rescue the unc-5(e53) null mutant. The data reveal partial functional requirements for the extracellular domains and identify a portion of the cytoplasmic juxtamembrane (JM) region as essential for rescue of migrations. When nine cytodomain tyrosines, including seven in the JM region, are mutated to phenylalanine, UNC-5 function and tyrosine phosphorylation are largely compromised. When F482 in the JM region of the mutant protein is reverted to tyrosine, UNC-5 tyrosine phosphorylation and in vivo function are largely recovered, suggesting that Y482 phosphorylation is critical to UNC-5 function in vivo. These data also show that part of the ZU-5 motif is required for UNC-40-independent signaling of UNC-5 (Killeen, 2002).
Two vertebrate homologs of UNC-5 have been identified that along with UNC-5 and the product of the mouse rostral cerebellar malformation gene (rcm) define a new subfamily of the immunoglobulin superfamily. Their messenger RNAs show prominent expression in various classes of differentiating neurons. UNC5H1 and UNC5H2 are more similar to one another (52% identity) than to UNC-5 (28% identity in each case). Both have two predicted immunoglobulin-like domains and two predicted thrombospondin type-1 repeats in their extracellular domains, a predicted membrane-spanning region, and a large intracellular domain. The cytoplasmic domains do not contain obvious motifs, but do possess a small region of homology to Zona Occludens-1, a protein that localizes to adherens junctions and is implicated in junction formation. ZO-1 contains PDZ domains, structures implicated in protein clustering. Unc5h1 transcripts are detected at the early stages of neural tube development in the ventral spinal cord. At embryonic day 11, when motor neurons begin to differentiate in that region, transcripts are present throughout the ventral spinal cord, excluding the midline floor region, but are most intense in the ventricular zone and at the lateral edges. Unc5h2 transcripts are not detected at significant levels in the spinal cord until E14, when they are found in the roof plate region. These genes are also expressed in non-neural structures. Netrin-1 can bind cells expressing these proteins (Leonardo, 1997).
Netrins are bifunctional: they attract some axons and repel others. Netrin receptors of the Deleted in Colorectal Cancer (DCC) family are implicated in attraction and those of the UNC5 family in repulsion, but genetic evidence also suggests involvement of the DCC protein UNC-40 in some cases of repulsion. To test whether these proteins form a receptor complex for repulsion, the attractive responses, mediated by DCC, of Xenopus spinal axons to netrin-1 were studied. Attraction is converted to repulsion by expression of UNC5 proteins in these cells. This repulsion requires DCC function; the UNC5 cytoplasmic domain is sufficient to effect the conversion, and repulsion can be initiated by netrin-1 binding to either UNC5 or DCC. The isolated cytoplasmic domains of DCC and UNC5 proteins interact directly, but this interaction is repressed in the context of the full-length proteins. Evidence is presented that netrin-1 triggers the formation of a receptor complex of DCC and UNC5 proteins and simultaneously derepresses the interaction between their cytoplasmic domains, thereby converting DCC-mediated attraction to UNC5/DCC-mediated repulsion (Hong, 1999).
To test whether the ectodomain of UNC5 proteins is required for repulsion, an examination was made of the effect of expressing a chimeric receptor in which the transmembrane and cytoplasmic domains of UNC5H2 (a human UNC5 homolog) were fused to the extracellular domain of DCC. Neurons expressing this DCC/UNC5H2 chimera show the same repulsive response to netrin-1 as do neurons expressing UNC5H2. To determine whether the transmembrane and cytoplasmic domains of UNC5H2 need to be fused to a netrin-binding ectodomain (as is the case for DCC), a chimeric receptor was examined in which the transmembrane and cytoplasmic domains of UNC5H2 were fused to the ectodomain of the NGF receptor TrkA, which does not bind netrin-1. Xenopus spinal neurons do not express TrkA endogenously and do not respond to an NGF gradient with either attraction or repulsion. Neurons expressing the TrkA/UNC5H2 chimera are repelled by netrin-1, a response that is blocked by the anti-DCC antibody; NGF has no effect on these neurons. These results suggested that the cytoplasmic domain of UNC5H2 might be sufficient for repulsion. This possibility was tested by generating a cDNA coding for the cytoplasmic domain of UNC5H2 preceded by a myristoylation sequence that targets cytoplasmic proteins to the inner leaflet of the plasma membrane. Neurons expressing this myristoylated UNC5H2 cytoplasmic domain construct exhibit marked repulsive responses to netrin-1. Thus, expression of the cytoplasmic domain of UNC5H2 is sufficient to convert netrin-mediated attraction to repulsion. It was then shown that netrin-1 triggers the formation of a heterodimeric or heteromultimeric complex involving DCC and UNC5H2 (Hong, 1999).
To further dissect the interaction between DCC and UNC5H2, attempts were made to identify regions in the DCC cytoplasmic domain required for the interaction. The first 46 amino acids are both necessary and sufficient for the interaction. Deletion of the juxtamembrane (JM) region (aas 1120-1148) does not abolish the interaction when performed in the context of the full-length cytoplasmic domain, and conversely, a construct comprising the JM domain alone does not suffice for the interaction. This shows that the JM domain is neither necessary nor sufficient for the interaction and identifies amino acids 1149-1166 as a key stretch required for the interaction. These 18 amino acids comprise the P1 domain, previously identified as a conserved domain among members of the DCC family. However, a construct comprising the P1 domain alone (aas 1149-1466) is not sufficient for the interaction. It is possible that the P1 domain does not fold properly in the absence of some adjacent sequences on either its amino- or carboxy-terminal ends; alternatively, the juxtamembrane region may be redundant with some other region of the cytoplasmic domain, with either one being sufficient but at least one being necessary (Hong, 1999).
Attempts were then made to identify the regions of UNC5 cytoplasmic domains required for DCC binding. Whereas a construct comprising UNC5H2 residues 707-946 is functional, a construct comprising residues 724-946 is not functional. Thus, residues 707-724 are required for binding the DCC cytoplasmic domain. These 18 residues are highly conserved among all previously described UNC5 proteins, and this domain has been termed the DB domain (since it is required for DCC binding). The DB domain is not the only domain required for repulsion, however. Deleting both the C-teminal Death Domain and 113 amino acids between the DB and the DD domains, but leaving the rest intact, including the DB domain, also results in a dominant-negative construct. Thus, sequences between the DD and DB domains are also important for repulsion, as could arise if these sequences are important for binding adaptor proteins. Deletion of the DB domain and all sequences carboxy terminal to it or deletion of all cytoplasmic domain sequences also results in the generation of dominant-negative constructs (Hong, 1999).
A paradox was raised by the finding that the isolated cytoplasmic domains of DCC and UNC5 proteins can interact, yet the full-length proteins do not coprecipitate in the absence of netrin-1. This raises the possibility that the interaction between cytoplasmic domains might be repressed in the context of the full-length proteins. To explore this possibility, a myristoylated cytoplasmic domain of one of the receptors (DCC or UNC5H2) was coexpressed with the full-length version of the other to see if they would coprecipitate. Full-length DCC coprecipitates with the myristoylated UNC5H2 cytoplasmic domain, but only in the presence of netrin-1. Similarly, only a low level of interaction of full-length UNC5H2 with the myristoylated DCC cytoplasmic domain is observed constitutively, and addition of netrin-1 dramatically increases the interaction. These results imply that in the absence of ligand, the UNC5H2 and DCC cytoplasmic domains are largely inaccessible to one another and that addition of netrin-1 causes some change in UNC5H2 and DCC that enables association of their cytoplasmic domains (Hong, 1999).
Why have a mechanism that switches from attraction to repulsion? The answer presumably lies in the fact that growth cones, as they navigate to their targets, change their responsiveness to guidance cues as they progress. Once a growth cone has reached a particular intermediate target, it must change its priorities in order to be able to move on to the next target. For example, commissural axons are initially attracted to the floor plate using netrin-1, but upon crossing the midline, they lose responsiveness to netrin-1. Since the axons continue to express DCC, the switching off must involve some other change. Another switch in growth cone sensitivity at the midline is the acquisition of Slit responsiveness by upregulation of expression of the Robo receptor in Drosophila. Although not yet demonstrated in vivo, it seems likely that there are circumstances where it is desirable not just to switch on or off responsiveness to a particular cue, but rather to convert the responsiveness from attraction to repulsion, to help move the growth cone along. The ability of one receptor to switch responses mediated by another receptor provides an economical means to achieve this end and avoid confusing the growth cone with simultaneous conflicting signals for attraction and repulsion (Hong, 1999 and references).
A recently described recessive mouse mutant, rostral cerebellar malformation (rcm/rcm), demonstrates a swaying gait at approximately 12 days of age. The mutant cerebellar (Cb) phenotype consists of cerebellar tissue that extends rostrally, beyond the usual distinct anterior cerebellar boundary, into the midbrain. Interestingly, the cerebellar ectopia occurs in the absence of any significant alterations in the distribution of nuclear groups within the brainstem. The ectopic Cb tissue is (1) adherent to the posterior and lateral aspects of the inferior colliculus and to the lateral aspect of the rostral brainstem and (2) contains acellular regions within the inner granular layer (igl) and ectopic, calbindin-immunoreactive Purkinje cells (PCs) deep relative to the igl. Within the Cb proper, PC organization is generally normal, as revealed by zebrin II immunoreactivity. In the ectopic Cb tissue PCs also exhibit a banded zebrin distribution. Analysis of the spinocerebellar projection in the mutant suggests a lobular distribution similar to that seen in the normal mouse. Within the anterior region, however, the normal parasagittal banding pattern is somewhat obscured. Spinocerebellar innervation of the ectopic Cb tissue exists, but it is almost exclusively confined to the region adjacent to the caudal inferior colliculus. In conjunction with the recent finding that the mutation appears to affect a UNC-5-like receptor protein for netrin-1 (a molecule that may be involved in axonal guidance and cell migration), these results suggest that this mutant is an important model for the analysis of cerebellar development and regionalization (Eisenman, 1998).
Mutation of the Unc5h3 (formally known as rcm) gene has important consequences on neuronal migration during cerebellar development. Unc5h3 transcripts are expressed early (embryonic day 8.5) in the hindbrain region and later in the cerebellar primordia. In Unc5h3 mutant embryos, both the development and initial migration of Purkinje cell progenitors occur as in wild-type controls. The rhombic lip, from which granule cell precursors arise, also appears to form normally in mutants. However, at E13.5, an abnormal subpopulation of granule cell and Purkinje cell precursors becomes detectable in rostral areas of the Unc5h3 mutant brain stem. These ectopic cerebellar cells increase in number and continue moving in a rostral direction throughout the remainder of embryogenesis and early stages of postnatal development invading the lateral regions of the pontine area and eventually the inferior colliculus. Cell proliferation markers demonstrate the mitotic nature of these subpial ectopic granule neurons, indicating the displacement of the rostral external germinal layer in mutant animals. These data suggest that establishment of the rostral cerebellar boundary may rely on chemorepulsive signaling events that require UNC5H3 expressed by cerebellar neurons and extracellular ligands that are functionally related to the UNC5H3-binding and guidance molecule, netrin1. Although the phenotype resulting from the Unc5h3 mutation is apparently limited to the formation of the cerebellum, additional sites of Unc5h3 expression are also found during development suggesting the compensatory function of other genes (Przyborski, 1998).
Migrating axons require the correct presentation of guidance molecules, often at multiple choice points, to find their target. Netrin 1, a bifunctional cue involved in both attracting and repelling axons, is involved in many cell migration and axon pathfinding processes in the CNS. The netrin 1 receptor DCC and its Caenorhabditis elegans homolog UNC-40 have been implicated in directing the guidance of axons toward netrin sources, whereas the C. elegans UNC-6 receptor, UNC-5, is necessary for migrations away from UNC-6. However, a role of vertebrate UNC-5 homologs in axonal migration has not been demonstrated. The Unc5h3 gene product, shown previously to regulate cerebellar granule cell migrations, also controls the guidance of the corticospinal tract, the major tract responsible for coordination of limb movements. Furthermore, corticospinal tract fibers respond differently to loss of UNC5H3. In addition, corticospinal tract defects are observed in mice homozygous for a spontaneous mutation that truncates the Dcc transcript. Postnatal day 0 netrin 1 mutant mice also demonstrate corticospinal tract abnormalities. Last, interactions between the Dcc and Unc5h3 mutations were observed in gene dosage experiments. This is the first evidence of an involvement in axon guidance for any member of the vertebrate unc-5 family and confirms that both the cellular and axonal guidance functions of C. elegans unc-5 have been conserved in vertebrates (Finger, 2002).
C. elegans UNC-5 and its mammalian homologs such as RCM are receptors for the secreted axon guidance cue UNC-6/netrin and are required to mediate the repulsive effects of UNC-6/netrin on growth cones. C. elegans UNC-5 and mouse RCM are phosphorylated on tyrosine in vivo. C. elegans UNC-5 tyrosine phosphorylation is reduced in unc-6 null mutants, and RCM tyrosine phosphorylation is induced by netrin-1 in transfected HEK-293 cells, demonstrating that phosphorylation of UNC-5 proteins is enhanced by UNC-6/netrin stimulation in both worms and mammalian cells. An activated Src tyrosine kinase induces phosphorylation of RCM at multiple cytoplasmic tyrosine residues creating potential binding sites for cytoplasmic signaling proteins. Indeed, the NH(2)-terminal SH2 domain of the Shp2 tyrosine phosphatase binds specifically to a Tyr(568) RCM phosphopeptide. Furthermore, Shp2 associates with RCM in a netrin-dependent manner in transfected cells, and co-immunoprecipitates with RCM from an embryonic mouse brain lysate. A Y568F mutant RCM receptor failed to bind Shp2 and was more highly phosphorylated on tyrosine than the wild type receptor. These results suggest that netrin-stimulated phosphorylation of RCM Tyr(568) recruits Shp2 to the cell membrane where it can potentially modify RCM phosphorylation and function (Tong, 2001).
Acting as receptors for netrin-1, the membrane receptors DCC and UNC5H have been shown to be crucial for axon guidance and neuronal migration. DCC has also been proposed as a dependence receptor inducing apoptosis in cells that are beyond netrin-1 availability. Dependence receptors create cellular states of dependence on their respective ligands by inducing apoptosis when unoccupied by ligand, but inhibiting apoptosis in the presence of ligand. The netrin-1 receptors UNC5H (UNC5H1, UNC5H2, UNC5H3) also act as dependence receptors. UNC5H receptors induce apoptosis, but this effect is blocked in the presence of netrin-1. Moreover, UNC5H receptors are cleaved in vitro by caspase in their intracellular domains. This cleavage may lead to the exposure of a fragment encompassing a death domain required for cell death induction in vivo. Evidence is presented that during development of the nervous system, the presence of netrin-1 is crucial to maintain survival of UNC5H- and DCC-expressing neurons, especially in the ventricular zone of the brainstem. Altogether, these results argue for a role of netrin-1 during the development of the nervous system, not only as a guidance cue but as a survival factor via its receptors DCC and UNC5H (Llambi, 2001).
Since UNC5H proteins are cleaved by protease and more specifically by caspase, an interesting model suggests that this cleavage allows the release or the exposure of a fragment that induces cell death. However, while expression of cleavage fragments issued from DCC, RET and AR allow cell death induction, expression of the UNC5H2 C-terminal fragment lying after Asp412 has no pro-apoptotic activity unless a myristoylation signal peptide is added. This observation then suggests the requirement of a sub-membrane localization of this fragment for cell death induction. Interestingly, both DCC and UNC5H proteins show oligomeric properties, which may explain heterodimeric binding of full-length UNC5H molecules with caspase-cleaved C-terminal fragments. One hypothesis then is that a heterodimeric complex allows, within membrane proximity, the exposure of the pro-apoptotic fragment lying downstream of the caspase cleavage site (Llambi, 2001).
It is of interest that this pro-apoptotic fragment contains a death domain. Such death domains have been found in various receptors including death receptors Fas and tumor necrosis factor receptor (TNFR) and the dependence receptor p75NTR. They are considered as 'adaptor' domains, allowing interaction of these receptors with 'adaptor' proteins. Death domains can be divided into two types (i.e. I or II) depending on their ability to homodimerize. Sequence alignment reveals that the UNC5H2 death domain is more related to the type II death domain of p75NTR than to the type I death domain of Fas, suggesting that the death domain of UNC5H probably displays no ability to homodimerize. In any case, both Fas and p75NTR death domains have been reported to be crucial for cell death induction. Remarkably, the deletion of the UNC5H2 death domain totally abrogates UNC5H2 pro-apoptotic activity. Taken together these results suggest that in the absence of netrin-1, UNC5H proteins induce cell death via the requirement of their death domain, which is probably exposed via the caspase cleavage. The role of this death domain is, however, completely unknown. The death domain of Fas allows, via the recruitment of the 'adaptor' molecule FADD, the formation of a caspase-activating complex that drives caspase-8 activation. It is also interesting to note that DCC, while without a death domain, recruits a caspase-activating complex allowing caspase-3 activation via the interaction of DCC with caspase-9. Whether the UNC5H death domain is involved in another caspase-activating complex through the recruitment of 'adaptor' molecules via its death domain needs now to be analysed further (Llambi, 2001).
Netrins are secreted molecules with roles in axonal growth and angiogenesis. The Netrin receptor UNC5B is required during embryonic development for vascular patterning, suggesting that it may also contribute to postnatal and pathological angiogenesis. unc5b is down-regulated in quiescent adult vasculature, but re-expressed during sprouting angiogenesis in matrigel and tumor implants. Stimulation of UNC5B-expressing neovessels with an agonist (Netrin-1) inhibits sprouting angiogenesis. Genetic loss of function of unc5b reduces Netrin-1-mediated angiogenesis inhibition. Expression of UNC5B full-length receptor also triggers endothelial cell repulsion in response to Netrin-1 in vitro, whereas a truncated UNC5B lacking the intracellular signaling domain fails to induce repulsion. These data show that UNC5B activation inhibits sprouting angiogenesis, thus identifying UNC5B as a potential anti-angiogenic target (Larrivée, 2007).
These results clearly show that UNC5B functions as a receptor for Netrin-1 in vivo, confirming and extending previous studies. It remains to be determined if Netrin-1 represents the (only) relevant in vivo ligand for UNC5B in mice. In zebrafish embryos, MO-mediated knockdown of unc5b or netrin-1a led to increased filopodial extensions and aberrant vessel branching of intersegmental vessels (ISV). The data in zebrafish are consistent with netrin-1a as a negative regulator of vessel branching. However, the results reported here do not exclude a possible proangiogenic role of Netrin-1. Nonendothelial cells in the ischemic area expressing unc5b (and perhaps other Netrin receptors) could respond to Netrin-1 and perhaps contribute to ischemic revascularization. In addition, no endothelial unc5b expression was observed following femoral artery ligation, and stimulation of UNC5B-negative endothelial cells by Netrin-1 could elicit proangiogenic responses. The present study provides multiple lines of evidence indicating that repulsive responses following Netrin-1 stimulation are consistently observed during neovascularization processes where unc5b is expressed, including tumor angiogenic sprouting. Development of UNC5B-selective agonists may be considered as potential therapeutic tools in anti-angiogenic strategies (Larrivée, 2007).
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