SEARCH · PubMed Health

Results for “Netrin Receptors”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources

PubMed2003

Netrin 1 mediates spinal cord oligodendrocyte precursor dispersal.

In spinal cord, oligodendrocyte precursors that give rise to myelin-forming cells originate in a restricted domain of the ventral ventricular zone. During development, these cells migrate widely throughout the spinal cord. Netrin 1 is expressed at the ventral ventricular zone during oligodendrocyte precursors emigration, and, in vitro, netrin 1 acts as chemorepellent and antagonizes platelet-derived growth factor (PDGF) chemoattraction. Oligodendrocyte precursors express the netrin receptors DCC and UNC5 and function-blocking anti-DCC antibody inhibits chemorepulsion of ventral spinal cord explants and netrin-secreting cells. In spinal cord slice preparations, addition of function-blocking anti-DCC antibody or netrin 1 dramatically inhibits oligodendrocyte precursor migration from the ventral ventricular zone. These data indicate the initial dispersal of oligodendrocyte precursors from their localized origin is guided by a chemorepellent response to netrin 1.

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↗

PubMed2005

Phosphatidylinositol transfer protein-alpha in netrin-1-induced PLC signalling and neurite outgrowth.

Neurite extension is essential for wiring the nervous system during development. Although several factors are known to regulate neurite outgrowth, the underlying mechanisms remain unclear. Here, we provide evidence for a role of phosphatidylinositol transfer protein-alpha (PlTPalpha) in neurite extension in response to netrin-1, an extracellular guidance cue. PlTPalpha interacts with the netrin receptor DCC (deleted in colorectal cancer) and neogenin. Netrin-1 stimulates PlTPalpha binding to DCC and to phosphatidylinositol (5) phosphate [Pl(5)P], increases its lipid-transfer activity and elevates hydrolysis of phosphatidylinositol bisphosphate (PlP2). In addition, the stimulated PIP2 hydrolysis requires PlTPalpha. Furthermore, cortical explants of PlTPalpha mutant mice are defective in extending neurites in response to netrin-1. Commissural neurons from chicken embryos expressing a dominant-negative PlTPalpha mutant show reduced axon outgrowth. Morpholino-mediated knockdown of PlTPalpha expression in zebrafish embryos leads to dose-dependent defects in motor-neuron axons and reduced numbers of spinal-cord neurons. Taken together, these results identify a crucial role for PlTPalpha in netrin-1-induced neurite outgrowth, revealing a signalling mechanism for DCC/neogenin and PlTPalpha regulation.

Animals↗

PubMed2003

Unwrapping glial biology: Gcm target genes regulating glial development, diversification, and function.

Glia are the most abundant cell type in the mammalian brain. They regulate neuronal development and function, CNS immune surveillance, and stem cell biology, yet we know surprisingly little about glia in any organism. Here we identify over 40 new Drosophila glial genes. We use glial cells missing (gcm) mutants and misexpression to verify they are Gcm regulated in vivo. Many genes show unique spatiotemporal responsiveness to Gcm in the CNS, and thus glial subtype diversification requires spatially or temporally restricted Gcm cofactors. These genes provide insights into glial biology: we show unc-5 (a repulsive netrin receptor) orients glial migrations and the draper gene mediates glial engulfment of apoptotic neurons and larval locomotion. Many identified Drosophila glial genes have homologs expressed in mammalian glia, revealing conserved molecular features of glial cells. 80% of these Drosophila glial genes have mammalian homologs; these are now excellent candidates for regulating human glial development, function, or disease.

Animals↗

PubMed2001

Binding of DCC by netrin-1 to mediate axon guidance independent of adenosine A2B receptor activation.

Netrins stimulate and orient axon growth through a mechanism requiring receptors of the DCC family. It has been unclear, however, whether DCC proteins are involved directly in signaling or are mere accessory proteins in a receptor complex. Further, although netrins bind cells expressing DCC, direct binding to DCC has not been demonstrated. Here we show that netrin-1 binds DCC and that the DCC cytoplasmic domain fused to a heterologous receptor ectodomain can mediate guidance through a mechanism involving derepression of cytoplasmic domain multimerization. Activation of the adenosine A2B receptor, proposed to contribute to netrin effects on axons, is not required for rat commissural axon outgrowth or Xenopus spinal axon attraction to netrin-1. Thus, DCC plays a central role in netrin signaling of axon growth and guidance independent of A2B receptor activation.

Animals↗

PubMed1998

Cloning and mapping of the UNC5C gene to human chromosome 4q21-q23.

The vertebrate Unc5 genes, like their Caenorhabditis elegans counterpart, define a family of putative netrin receptors. One member of this family, Unc5h3, has been shown to have an important role during cell migration in the developing murine cerebellum. Mice homozygous for mutations in Unc5h3 are ataxic and have cerebellar hypoplasia and laminar structure defects. In addition, these mice have ectopic granule and Purkinje cells in the midbrain and brainstem. We have identified the human homologue of this gene, UNC5C, and shown it to have a restricted expression pattern in adult human tissues. By radiation hybrid analysis, we have determined that UNC5C localizes to chromosome 4q21-q23 between markers D4S1557 and D4S836 and is closely linked to the Parkinson disease gene.

Adult↗

PubMed2002

Deleted in colorectal carcinoma and differentially expressed integrins mediate the directional migration of neural precursors in the rostral migratory stream.

Precursors of the olfactory interneurons migrate from the subventricular zone via the rostral migratory stream (RMS). To investigate the molecular mechanisms by which RMS cells migrate, we used a slice preparation, which allows the migrating cells to be imaged at very high temporal and spatial resolution in the presence of added inhibitors. Using immunohistochemistry, we first determined that the alpha1-, beta8-, and beta1-integrin subunits and the alpha5- and gamma1-laminin subunits are expressed during embryonic day 16 to the early postnatal stage. During early postnatal days, alpha(v)- and beta6-integrins appeared, and their expression persisted throughout adulthood. The migrating cells also expressed the netrin receptors neogenin and Deleted in Colorectal Carcinoma (DCC). Netrin-1 is expressed in olfactory mitral cells. Anti-integrin antibodies inhibited the production of protrusions as well as cellular translocation. In contrast, anti-DCC antibodies primarily altered the direction of the protrusions; consequently, the migration was no longer unidirectional, and the speed was reduced. Thus, the interaction of DCC, possibly through an interaction with netrin-1, contributes to the direction of migration by regulating the formation of directed protrusions. In contrast, the integrins function in production of protrusions and cellular translocation, with different integrins participating at different developmental stages.

Aging↗

PubMed2000

Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor.

The netrins, a family of laminin-related secreted proteins, are critical in controlling axon elongation and pathfinding. The DCC (for deleted in colorectal cancer) protein was proposed as a receptor for netrin-1 in the light of many observations including the inhibition of netrin-1-mediated axon outgrowth and attraction in the presence of an anti-DCC antiserum, the similitude of nervous system defects in DCC and netrin-1 knockout mice and the results of receptor swapping experiments. Previous studies have failed to show a direct interaction of DCC with netrin-1 (ref. 10), suggesting the possibility of an additional receptor or co-receptor. Here we show that DCC interacts with the membrane-associated adenosine A2b receptor, a G-protein-coupled receptor that induces cAMP accumulation on binding adenosine. We show that A2b is actually a netrin-1 receptor and induces cAMP accumulation on binding netrin-1. Finally, we show that netrin-1-dependent outgrowth of dorsal spinal cord axons directly involves A2b. Together our results indicate that the growth-promoting function of netrin-1 may require a receptor complex containing DCC and A2b.

Animals↗

PubMed2006

Netrin/DCC-mediated attraction of vagal sensory axons to the fetal mouse gut.

Vagal sensory axons and migrating neural crest-derived precursor cells follow similar pathways to reach the gut. The crest-derived cells express the netrin receptor deleted in colorectal cancer (DCC) and migrate toward netrins expressed by the intestinal mucosa and pancreas; this attraction is required for the formation of submucosal and pancreatic ganglia. We tested the hypothesis that enteric netrins also attract vagal sensory fibers. These axons were located as a function of age in fetal mice by applying the lipophilic tracer 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) bilaterally to nodose ganglia. DiI-labeled axons were found in the esophagus and proximal stomach by E12 and, more distally, in the small bowel at E14-E16. Transcripts encoding DCC were expressed in the nodose ganglia of mice from E12 to adulthood but were developmentally regulated. Paraesophageal anterior and posterior vagal trunks were DCC immunoreactive from E12 to E16. Transcripts encoding netrin-1 were expressed in the developing foregut and midgut; netrin-1 immunoreactivity was detected in the outer gut mesenchyme and mucosal epithelium. Neurites from explanted E14 nodose ganglia grew selectively toward cocultured E14 distal foregut explants (P < 0.01). Antibodies to DCC specifically abolished this preferential outgrowth (P < 0.05). Nodose axons also grew selectively toward cocultured netrin-secreting 293-EBNA cells (P < 0.005); antibodies to DCC again blocked this preferential outgrowth (P < 0.05). These data suggest that netrins, which are expressed in the bowel, attract DCC-expressing vagal sensory axons.

Age Factors↗

PubMed2002

Netrins.

Explore the source record for details and available documents.

Animals↗

PubMed2003

Robo and Frazzled/DCC mediate dendritic guidance at the CNS midline.

Neuronal connectivity is established by the axo-dendritic polarity, correct guidance and targeting of neurons. Unlike for axons, the mechanisms responsible for directed outgrowth of dendrites are not well understood. Using single-cell labeling, we describe specific guidance defects in dendrites of identified neurons in frazzled, robo, netrin and commissureless mutant embryos of Drosophila melanogaster. We found that the cell-surface molecules Frazzled and Robo work as guidance molecules not only for axons but also for dendrites as they navigate within the CNS. Furthermore, we report that each neuron showed a cell-autonomous and independent use of guidance molecules.

Animals↗

PubMed1998

DCC and netrins.

Recent advances highlight the versatility and complexity of this highly conserved axon and cell migration guidance system. Characterization of netrin mutant phenotypes in worm, fly and mouse all suggest that netrins play local as well as long-range roles in guidance. Evidence from multiple sources also indicates that the netrin receptor DCC can mediate both attractive and repulsive responses to netrins.

Caenorhabditis elegans Proteins↗

PubMed2006

Neogenin: one receptor, many functions.

Neogenin is a multifunctional transmembrane receptor belonging to the immunoglobulin superfamily. It displays identical secondary structure to deleted in colorectal cancer (DCC), a netrin receptor that is involved in axon guidance and cell survival. Like DCC, neogenin is able to transduce signals elicited by netrin. These neogenin-netrin interactions have been implicated in tissue morphogenesis, angiogenesis, myoblast differentiation and most recently in axon guidance. Neogenin is also a receptor for repulsive guidance molecule, a glycosylphosphatidylinositol-linked protein involved in neuronal differentiation, apoptosis and repulsive axon guidance. Numerous studies have been started to elucidate the in vivo functions of neogenin, and its role in multiple aspects of development and homeostasis.

Animals↗

PubMed2001

Expression of netrin-1 and its receptors DCC and UNC-5H2 after axotomy and during regeneration of adult rat retinal ganglion cells.

Netrins are a family of chemotropic factors that guide axon outgrowth during development; however, their function in the adult CNS remains to be established. We examined the expression of the netrin receptors DCC and UNC5H2 in adult rat retinal ganglion cells (RGCs) after grafting a peripheral nerve (PN) to the transected optic nerve and following optic nerve transection alone. In situ hybridization revealed that both Dcc and Unc5h2 mRNAs are expressed by normal adult RGCs. In addition, netrin-1 was found to be constitutively expressed by RGCs. Quantitative analysis using in situ hybridization demonstrated that both Dcc and Unc5h2 were down-regulated by RGCs following axotomy. In the presence of an attached PN graft, Dcc and Unc5h2 were similarly down-regulated in surviving RGCs regardless of their success in regenerating an axon. Northern blot analysis demonstrated expression of netrin-1 in both optic and sciatic nerve, and Western blot analysis revealed the presence of netrin protein in both nerves. Immunohistochemical analysis indicated that netrin protein was closely associated with glial cells in the optic nerve. These results suggest that netrin-1, DCC, and UNC5H2 may contribute to regulating the regenerative capacity of adult RGCs.

Animals↗

PubMed1997

DCC's function takes shape in the nervous system.

Deleted in colorectal cancer (DCC), a candidate tumor-suppressor gene, has recently been found to encode a netrin receptor required for axon guidance in vitro. Mutations in Caenorhabditis elegans and Drosophila genes encoding DCC-related proteins affect axon guidance, and these phenotypes resemble those of mutations in netrin genes. Netrins and their DCC-related receptors thus play an evolutionarily conserved role in midline guidance, and DCC may be required more generally for cellular morphogenesis.

Amino Acid Sequence↗

PubMed1997

Netrin-1 and DCC mediate axon guidance locally at the optic disc: loss of function leads to optic nerve hypoplasia.

Embryonic retinal ganglion cell (RGC) axons must extend toward and grow through the optic disc to exit the eye into the optic nerve. In the embryonic mouse eye, we found that immunoreactivity for the axon guidance molecule netrin-1 was specifically on neuroepithelial cells at the disk surrounding exiting RGC axons, and RGC axons express the netrin receptor, DCC (deleted in colorectal cancer). In vitro, anti-DCC antibodies reduced RGC neurite outgrowth responses to netrin-1. In netrin-1- and DCC-deficient embryos, RGC axon pathfinding to the disc was unaffected; however, axons failed to exit into the optic nerve, resulting in optic nerve hypoplasia. Thus, netrin-1 through DCC appears to guide RGC axons locally at the optic disc rather than at long range, apparently reflecting the localization of netrin-1 protein to the vicinity of netrin-1-producing cells at the optic disc.

Animals↗

PubMed1999

SDQR migrations in Caenorhabditis elegans are controlled by multiple guidance cues and changing responses to netrin UNC-6.

The netrin guidance cue, UNC-6, and the netrin receptors, UNC-5 and UNC-40, guide SDQR cell and axon migrations in C. elegans. In wild-type larvae, SDQR migrations are away from ventral UNC-6-expressing cells, suggesting that UNC-6 repels SDQR. In unc-6 null larvae, SDQR migrations are towards the ventral midline, indicating a response to other guidance cues that directs the migrations ventrally. Although ectopic UNC-6 expression dorsal to the SDQR cell body would be predicted to cause ventral SDQR migrations in unc-6 null larvae, in fact, more migrations are directed dorsally, suggesting that SDQR is not always repelled from the dorsal source of UNC-6. UNC-5 is required for dorsal SDQR migrations, but not for the ventral migrations in unc-6 null larvae. UNC-40 appears to moderate both the response to UNC-6 and to the other cues. Our results show that SDQR responds to multiple guidance cues and they suggest that, besides UNC-6, other factors influence whether an UNC-6 responsive cell migrates toward or away from an UNC-6 source in vivo. We propose that multiple signals elicited by the guidance cues are integrated and interpreted by SDQR and that the response to UNC-6 can change depending on the combination of cues encountered during migration. These responses determine the final dorsoventral position of the SDQR cell and axon.

Animals↗

PubMed2005

Slit-roundabout signaling neutralizes netrin-Frazzled-mediated attractant cue to specify the lateral positioning of longitudinal axon pathways.

An extending axon growth cone is subjected to attractant and repellent cues. It is not clear how these growth cones discriminate the two opposing forces and select their projection paths. Here, we report that in the Drosophila nerve cord the growth cones of longitudinal tracts are subjected to attraction by the Netrin-Frazzled pathway. However, the midline Slit neutralizes this pathway in a Robo-dependent manner and prevents Netrin-Frazzled-mediated attraction of longitudinal tracts. Our results suggest that the loss of a neutralizing effect on the Netrin-mediated attraction is responsible for the longitudinal tracts entering the midline in slit mutants as opposed to a loss of repulsion as is currently believed. This effect is not via a direct inhibition of Frazzled by Robo; instead, it is at a level downstream of Frazzled. Thus, the growth cones of longitudinal tracts subjected to two opposing forces are able to block one with the other and specify their correct lateral positioning along the midline.

Animals↗