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PubMed2005

Localization of immunoreactivity for deleted in colorectal cancer (DCC), the receptor for the guidance factor netrin-1, in ventral tier dopamine projection pathways in adult rodents.

DCC (deleted in colorectal cancer)-the receptor of the netrin-1 neuronal guidance factor-is expressed and is active in the central nervous system (CNS) during development, but is down-regulated during maturation. The substantia nigra contains the highest level of netrin-1 mRNA in the adult rodent brain, and corresponding mRNA for DCC has also been detected in this region but has not been localized to any particular neuron type. In this study, an antibody raised against DCC was used to determine if the protein was expressed by adult dopamine neurons, and identify their distribution and projections. Significant DCC-immunoreactivity was detected in midbrain, where it was localized to ventrally displaced A9 dopamine neurons in the substantia nigra, and ventromedial A10 dopamine neurons predominantly situated in and around the interfascicular nucleus. Strong immunoreactivity was not detected in dopamine neurons found elsewhere, or in non-dopamine-containing neurons in the midbrain. Terminal fields selectively labeled with DCC antibody corresponded to known nigrostriatal projections to the dorsolateral striatal patches and dorsomedial shell of the accumbens, and were also detected in prefrontal cortex, septum, lateral habenular and ventral pallidum. The unique distribution of DCC-immunoreactivity in adult ventral midbrain dopamine neurons suggests that netrin-1/DCC signaling could function in plasticity and remodeling previously identified in dopamine projection pathways. In particular, a recent report that DCC is regulated through the ubiquitin-proteosome system via Siah/Sina proteins, is consistent with a potential involvement in genetic and sporadic forms of Parkinson's disease.

Animals↗

PubMed1999

Chimeric axon guidance receptors: the cytoplasmic domains of slit and netrin receptors specify attraction versus repulsion.

Frazzled (Fra) is the DCC-like Netrin receptor in Drosophila that mediates attraction; Roundabout (Robo) is a Slit receptor that mediates repulsion. Both ligands are expressed at the midline; both receptors have related structures and are often expressed by the same neurons. To determine if attraction versus repulsion is a modular function encoded in the cytoplasmic domain of these receptors, we created chimeras carrying the ectodomain of one receptor and the cytoplasmic domain of the other and tested their function in transgenic Drosophila. Fra-Robo (Fra's ectodomain and Robo's cytoplasmic domain) functions as a repulsive Netrin receptor; neurons expressing Fra-Robo avoid the Netrin-expressing midline and muscles. Robo-Fra (Robo's ectodomain and Fra's cytoplasmic domain) is an attractive Slit receptor; neurons and muscle precursors expressing Robo-Fra are attracted to the Slit-expressing midline.

Animals↗

PubMed2005

Requirement of TRPC channels in netrin-1-induced chemotropic turning of nerve growth cones.

Ion channels formed by the TRP (transient receptor potential) superfamily of proteins act as sensors for temperature, osmolarity, mechanical stress and taste. The growth cones of developing axons are responsible for sensing extracellular guidance factors, many of which trigger Ca2+ influx at the growth cone; however, the identity of the ion channels involved remains to be clarified. Here, we report that TRP-like channel activity exists in the growth cones of cultured Xenopus neurons and can be modulated by exposure to netrin-1 and brain-derived neurotrophic factor, two chemoattractants for axon guidance. Whole-cell recording from growth cones showed that netrin-1 induced a membrane depolarization, part of which remained after all major voltage-dependent channels were blocked. Furthermore, the membrane depolarization was sensitive to blockers of TRP channels. Pharmacological blockade of putative TRP currents or downregulation of Xenopus TRP-1 (xTRPC1) expression with a specific morpholino oligonucleotide abolished the growth-cone turning and Ca2+ elevation induced by a netrin-1 gradient. Thus, TRPC currents reflect early events in the growth cone's detection of some extracellular guidance signals, resulting in membrane depolarization and cytoplasmic Ca2+ elevation that mediates the turning of growth cones.

Animals↗

PubMed1999

The Deleted in Colorectal Cancer netrin guidance system: a molecular strategy for neuronal navigation.

1. Neuronal migration is one of the principal events in laying out the architectural plan of the embryonic central nervous system (CNS). In addition, the correct navigation of axonal growth cones to their specific targets is essential for the establishment of the intricate network of axon projections found within the mature CNS. 2. The Deleted in Colorectal Cancer (DCC) guidance receptor, together with its ligands, the netrins, is now emerging as a major navigational system driving both neuronal and axonal migrations. Members of the netrin family of secreted guidance cues are also likely to be ligands for a second DCC-like receptor, neogenin. 3. The present paper reviews the current understanding of DCC-netrin-dependent axon pathfinding within the embryonic spinal cord and suggests novel modes of action for both DCC and neogenin.

Animals↗

PubMed2002

The adaptor protein Nck-1 couples the netrin-1 receptor DCC (deleted in colorectal cancer) to the activation of the small GTPase Rac1 through an atypical mechanism.

Netrins are a family of secreted proteins that guide the migration of cells and axonal growth cones during development. DCC (deleted in colorectal cancer) is a receptor for netrin-1 implicated in mediating these responses. Here, we show that DCC interacts constitutively with the SH3/SH2 adaptor Nck in commissural neurons. This interaction is direct and requires the SH3 but not SH2 domains of Nck-1. Moreover, both DCC and Nck-1 associate with the actin cytoskeleton, and this association is mediated by DCC. A dominant negative Nck-1 inhibits the ability of DCC to induce neurite outgrowth in N1E-115 cells and to activate Rac1 in fibroblasts in response to netrin-1. These studies provide evidence for an important role of mammalian Nck-1 in a novel signaling pathway from an extracellular guidance cue to changes in the actin-based cytoskeleton responsible for axonal guidance.

3T3 Cells↗

PubMed2005

The Abelson tyrosine kinase, the Trio GEF and Enabled interact with the Netrin receptor Frazzled in Drosophila.

The attractive Netrin receptor Frazzled (Fra), and the signaling molecules Abelson tyrosine kinase (Abl), the guanine nucleotide-exchange factor Trio, and the Abl substrate Enabled (Ena), all regulate axon pathfinding at the Drosophila embryonic CNS midline. We detect genetic and/or physical interactions between Fra and these effector molecules that suggest that they act in concert to guide axons across the midline. Mutations in Abl and trio dominantly enhance fra and Netrin mutant CNS phenotypes, and fra;Abl and fra;trio double mutants display a dramatic loss of axons in a majority of commissures. Conversely, heterozygosity for ena reduces the severity of the CNS phenotype in fra, Netrin and trio,Abl mutants. Consistent with an in vivo role for these molecules as effectors of Fra signaling, heterozygosity for Abl, trio or ena reduces the number of axons that inappropriately cross the midline in embryos expressing the chimeric Robo-Fra receptor. Fra interacts physically with Abl and Trio in GST-pulldown assays and in co-immunoprecipitation experiments. In addition, tyrosine phosphorylation of Trio and Fra is elevated in S2 cells when Abl levels are increased. Together, these data suggest that Abl, Trio, Ena and Fra are integrated into a complex signaling network that regulates axon guidance at the CNS midline.

Animals↗

PubMed2006

Netrin 1 regulates ventral tangential migration of guidepost neurons in the lateral olfactory tract.

In the developing nervous system, functional neural networks are constructed with intricate coordination of neuronal migrations and axonal projections. We have previously reported a ventral tangential migration of a special type of cortical neurons, lot cells, in the mouse embryo. These neurons originate from the ventricular zone of the entire neocortex, tangentially migrate in the surface layer of the neocortex into the ventral direction, align in the future pathway of the lateral olfactory tract (LOT) and eventually guide the projection of LOT axons. In this study, we developed an organotypic culture system to investigate the regulation of this cell migration in the developing telencephalon. Our data show that the neocortex contains the signals that direct lot cells ventrally, that the ganglionic eminence excludes lot cells by repelling the migration and that lot cells are attracted to netrin 1, an axon guidance factor. Furthermore, we demonstrate that mutations in the genes encoding netrin 1 and its functional receptor Dcc lead to inappropriate distribution of lot cells and subsequent partial disruption of LOT projection. These results suggest that netrin 1 regulates the migration of lot cells and LOT projections, possibly by ensuring the correct distribution of these guidepost neurons.

Animals↗

PubMed2005

DCC association with lipid rafts is required for netrin-1-mediated axon guidance.

During development, axons migrate long distances in responses to attractive or repulsive signals that are detected by their growth cones. One of these signals is mediated by netrin-1, a diffusible laminin-related molecule that both attracts and repels growth cones via interaction with its receptor DCC (deleted in colorectal cancer). Here we show that DCC in both commissural neurons and immortalized cells, is partially associated with cholesterol- and sphingolipid-enriched membrane domains named lipid rafts. This localization of DCC in lipid rafts is mediated by the palmitoylation within its transmembrane region. Moreover, this raft localization of DCC is required for netrin-1-induced DCC-dependent ERK activation, and netrin-1-mediated axon outgrowth requires lipid raft integrity. Thus, the presence of axon guidance-related receptors in lipid rafts appears to be a crucial pre-requisite for growth cone response to chemo-attractive or repulsive cues.

Animals↗

PubMed2004

Netrin-1 and semaphorin 3A promote or inhibit cortical axon branching, respectively, by reorganization of the cytoskeleton.

In many CNS pathways, target innervation occurs by axon branching rather than extension of the primary growth cone into targets. To investigate mechanisms of branch formation, we studied the effects of attractive and inhibitory guidance cues on cortical axon branching. We found that netrin-1, which attracts cortical axons, and FGF-2 increased branching by >50%, whereas semaphorin 3A (Sema3A), which repels cortical axons, inhibited branching by 50%. Importantly, none of the factors affected axon length significantly. The increase in branching by FGF-2 and the inhibition of branching by Sema3A were mediated by opposing effects on the growth cone (expansion vs collapse) and on the cytoskeleton. FGF-2 increased actin polymerization and formation of microtubule loops in growth cones over many hours, whereas Sema3A depolymerized actin filaments, attenuated microtubule dynamics, and collapsed microtubule arrays within minutes. Netrin-1 promoted rapid axon branching, often without involving the growth cone. Branches formed de novo on the axon shaft within 30 min after local application of netrin-1, which induced rapid accumulation of actin filaments in filopodia. Importantly, increased actin polymerization and microtubule dynamics were necessary for axon branching to occur. Taken together, these results show that guidance factors influence the organization and dynamics of the cytoskeleton at the growth cone and the axon shaft to promote or inhibit axon branching. Independent of axon outgrowth, axon branching in response to guidance cues can occur over different time courses by different cellular mechanisms.

Actins↗

PubMed2002

MAX-1, a novel PH/MyTH4/FERM domain cytoplasmic protein implicated in netrin-mediated axon repulsion.

The netrin UNC-6 repels motor axons by activating the UNC-5 receptor alone or in combination with the UNC-40/DCC receptor. In a genetic screen for C. elegans mutants exhibiting partial defects in motor axon projections, we isolated the max-1 gene (required for motor neuron axon guidance). max-1 loss-of-function mutations cause fully penetrant but variable axon guidance defects. Mutations in unc-5 and unc-6, but not in unc-40, dominantly enhance the mutant phenotypes of max-1, whereas overexpression of unc-5 or unc-6, but not of unc-40, bypasses the requirement for max-1. MAX-1 proteins contain PH, MyTH4, and FERM domains and appear to be localized to neuronal processes. Human MAX-1 and UNC5H2 colocalize in discrete subcellular regions of transfected cells. Our results suggest a possible role for MAX-1 in netrin-induced axon repulsion by modulating the UNC-5 receptor signaling pathway.

Amino Acid Sequence↗

PubMed1996

Functions of netrins and semaphorins in axon guidance.

Neuronal growth cones respond to both contact-mediated and chemotropic guidance cues; these cues can be either attractive or repulsive. This past year has seen further characterization of two gene families implicated in long-range chemoattraction and chemorepulsion: the netrins and the semaphorins. Analysis of invertebrate members of these gene families demonstrates in vivo how netrins play multiple roles in axonal guidance in Caenorhabditis elegans, how specific domains of the netrin molecule confer attractive and repulsive guidance cues, and how semaphorins can function to generate neuromuscular specificity.

Animals↗

PubMed2003

Quantification of expression of netrins, slits and their receptors in human prostate tumors.

Recently, DCC (Deleted in Colorectal Cancer) protein has been forwarded as a receptor for netrin. The Netrin/DCC complex is critical for axon guidance and cell migration. In the developing nervous system, netrin protein secreted by midline cells attracts commissural axons by activating the DCC receptor on growth cones. This attraction can be switched to repulsion or silenced completely, depending on the DCC binding partner. The potential suppressor function of DCC in prostate tumorigenesis, through a still unknown mechanism, prompted us to quantify the expression of several genes involved in this axon guidance pathway. The relative expression levels of DCC, NEO1, NTN1, NTN2L, NTN4, UNC5C, Slit1, Slit2, Slit3, Robo1 and Robo2 were simultaneous quantified in 48 tumors and 7 normal prostate tissues by using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). A reduction in DCC, NEO1, NTN1 and NTN4 expression was observed in prostate tumors, while many of the same prostate tumors over-expressed either Slit genes or their receptors, Robo.

Adenocarcinoma↗

PubMed2004

Rat neurological mutations cerebellar vermis defect and hobble are caused by mutations in the netrin-1 receptor gene Unc5h3.

Rats homozygous for the spontaneous cerebellar vermis defect mutation (cvd) or hobble mutation (hob) exhibit cerebellar and midbrain defects, possibly as a result of abnormal neuronal migration. Both mutant rats demonstrate laminar structure abnormalities in the fused cerebellar hemispheres and ectopic cerebellar tissues in the cerebello-pontine junction. Previous genetic studies showed that cvd and hob were allelic and suggested that Unc5h3, the causative gene of the mouse rostral cerebellar malformation (rcm) mutation, was a strong candidate for both cvd and hob. Unc5h3 encodes a receptor mediating the repulsive action for Netrin-1 and has an important role during cell migration in the developing murine cerebellum. Here, we describe positional candidate cloning of cvd and hob, and identified cvd and hob mutations in the rat Unc5h3. The cvd mutation is a nucleotide conversion of G to T resulting in a premature termination at codon 451 of the UNC5H3 protein. The hob mutation is a 2-bp insertion resulting in a frame shift from codon 312 and a premature termination at codon 385 of the UNC5H3 protein. Both cvd and hob mutations are predicted to lead to truncated UNC5H3 proteins lacking their cytoplasmic region required for Netrin-Unc5h3 signaling pathway. Therefore, we conclude that Unc5h3 is causative gene of both cvd and hob mutant phenotypes. Rats homozygous for Unc5h3cvd or Unc5h3hob are the first mammalian Unc5h3 mutant model other than Unc5h3rcm/rcm mice, and will provide a useful tool for further understanding of the biological function of Unc5h3.

Animals↗

PubMed1997

Expression and regulation of a netrin homologue in the zebrafish embryo.

Proteins of the Netrin family have been implicated in axon guidance in both C. elegans and vertebrates. Here, we report the cloning and expression analysis of a zebrafish netrin homologue (net1). net1 is expressed in the floor plate and the anterior ventral neural tube. Its expression is ectopically induced by misexpression of sonic hedgehog (shh) and a dominant negative mutant of the regulatory subunit of protein kinase A (dnReg). Ectopic activation of net1, however, is restricted to distinct regions in the brain. Upon overexpression of shh or dnReg in cyclops mutants, which have strongly impaired net1 expression in the ventral neural tube, rescue of net1 expression was observed in the brain but not in the spinal cord. Ectopic expression of dnReg and Shh protein can be detected at high levels throughout injected embryos from pre-gastrula stages onwards suggesting that the competence of the neural plate to respond to Shh signalling activity differs regionally. Similar to net1, axial, the zebrafish homologue of mammalian HNF3beta, which is also expressed along the ventral neural tube, is ectopically induced in the brain of embryos injected with dnReg mRNA. Neurons differentiate normally within domains of ectopic net1 and axial expression. Thus, dorsal neuronal differentiation appears to be unaffected despite co-expression of a gene program specific for the ventral neural tube. This also suggests that these ectopically expressing regions have not differentiated into floor plate.

Amino Acid Sequence↗

PubMed1997

Axon guidance: netrin receptors are revealed.

Netrins are molecules that guide growing axons and that are strikingly similar in sequence and in function in flies, nematodes and vertebrates. Now, members of a family of netrin receptors have been identified in all three animal groups and shown to have crucial, conserved roles in axon navigation.

Animals↗

PubMed2006

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

In addition to their role as chemorepellent netrin-1 receptors, UNC5 proteins may mediate cell death because they induce apoptosis in cultured cells. To test this in vivo, we generated Unc5a (formerly Unc5h1) knockout mice and found that this deletion decreased apoptosis and increased the number of neurons in the spinal cord. In contrast, loss of netrin-1 (Ntn1) did not affect the amount of apoptosis, suggesting that NTN1 is not required for neuronal apoptosis in vivo.

Animals↗

PubMed2004

Netrin 1-mediated chemoattraction regulates the migratory pathway of LHRH neurons.

Luteinizing hormone-releasing hormone (LHRH) neurons migrate from the vomeronasal organ (VNO) to the forebrain in all mammals studied. In mice, the direction of LHRH neuron migration is dependent upon axons that originate in the VNO, but bypass the olfactory bulb and project caudally into the basal forebrain. Thus, factors that guide this unique subset of vomeronasal axons that comprise the caudal vomeronasal nerve (cVNN) are candidates for regulating the migration of LHRH neurons. We previously showed that deleted in colorectal cancer (DCC) is expressed by neurons that migrate out of the VNO during development [Schwarting et al. (2001) J. Neurosci., 21, 911-919]. We examined LHRH neuron migration in Dcc-/- mice and found that trajectories of the cVNN and positions of LHRH neurons are abnormal. Here we extend these studies to show that cVNN trajectories and LHRH cell migration in netrin 1 (Ntn1) mutant mice are also abnormal. Substantially reduced numbers of LHRH neurons are found in the basal forebrain and many LHRH neurons migrate into the cerebral cortex of Ntn1 knockout mice. In contrast, migration of LHRH cells is normal in Unc5h3rcm mutant mice. These results are consistent with the idea that the chemoattraction of DCC+ vomeronasal axons by a gradient of netrin 1 protein in the ventral forebrain guides the cVNN, which, in turn, determines the direction of LHRH neuron migration in the forebrain. Loss of function through a genetic deletion in either Dcc or Ntn1 results in the migration of many LHRH neurons to inappropriate destinations.

Animals↗

PubMed2001

Upregulation of the netrin receptor (DCC) gene during activation of b lymphocytes and modulation by interleukins.

The DCC (deleted in colon cancer) gene has a brain restricted high expression pattern. It encodes a transmembrane protein of the immunoglobulin superfamily identified as the netrin-1 receptor. It might be a member of the so called "brain-lymphoid" molecules, which control key cell surface events. To test this hypothesis we have assessed the DCC mRNA level in human normal and malignant myeloid and lymphoid cells. A high mRNA content has been observed only in mature B cells at the secreting or presecreting stage. Expression of DCC was also assessed in the anti-CD40 model of immunopoiesis. Activation of purified tonsillar B cells by anti-CD 40 antibody strongly increased the DCC mRNA level and this effect was dramatically enhanced by the association of IL-2 + IL-10, which is a potent and selective in vitro inducer of the B cell memory phenotype. In contrast no effect has been detected after activation of T cells by anti-CD3. These data suggest that the DCC encoded netrin receptor is involved in B cell immunopoiesis.

Adult↗