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At least 19 recordsLinked to original sources

PubMed2001

Short- and long-range repulsion by the Drosophila Unc5 netrin receptor.

Netrins are bifunctional guidance molecules, attracting some axons and repelling others. They act through receptors of the DCC and UNC5 families. DCC receptors have been implicated in both attraction and repulsion by Netrins. UNC5 receptors are required only for repulsion. In Drosophila, Netrins are expressed by midline cells of the CNS and by specific muscles in the periphery. They attract commissural and motor axons expressing the DCC family receptor Frazzled. Here we report the identification of the Drosophila Unc5 receptor, and show that it is a repulsive Netrin receptor likely to contribute to motor axon guidance. Ectopic expression of Unc5 on CNS axons can elicit either short- or long-range repulsion from the midline. Both short- and long-range repulsion require Netrin function, but only long-range repulsion requires Frazzled.

Amino Acid Sequence↗

PubMed2000

Lesion-induced regulation of netrin receptors and modification of netrin-1 expression in the retina of fish and grafted rats.

To determine whether netrin receptors (DCC, UNC5H1, UNC5H2) and netrin-1 are present in the adult rat retina and may affect regeneration of retinal ganglion cell (RGC) axons into peripheral nerve (PN) grafts, in situ hybridization (ISH) and immunostaining experiments were performed in normal and operated rats. Netrin-1 expression was not found in the optic nerve head of adult rats, normal and postlesion, but appeared transiently at 7 and 14 days after PN grafting. ISH signals of netrin receptors, however, disappeared from RGCs within 2 days after lesion and remained absent after PN grafting except for UNC5H2, which transiently occurred in a few RGCs. Netrin-1 expression was observed in the optic nerve head of adult fish, normal and postlesion, and the netrin-1 Fc fusion protein bound to young growing and all regenerating axons. Thus, the netrin-1-dependent guidance system continues to function in fish but apparently no longer operates in adult rats.

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PubMed1999

Netrin-3, a mouse homolog of human NTN2L, is highly expressed in sensory ganglia and shows differential binding to netrin receptors.

The netrins comprise a small phylogenetically conserved family of guidance cues important for guiding particular axonal growth cones to their targets. Two netrin genes, netrin-1 and netrin-2, have been described in chicken, but in mouse so far a single netrin gene, an ortholog of chick netrin-1, has been reported. We report the identification of a second mouse netrin gene, which we name netrin-3. Netrin-3 does not appear to be the ortholog of chick netrin-2 but is the ortholog of a recently identified human netrin gene termed NTN2L ("netrin-2-like"), as evidenced by a high degree of sequence conservation and by chromosomal localization. Netrin-3 is expressed in sensory ganglia, mesenchymal cells, and muscles during the time of peripheral nerve development but is largely excluded from the CNS at early stages of its development. The murine netrin-3 protein binds to netrin receptors of the DCC (deleted in colorectal cancer) family [DCC and neogenin] and the UNC5 family (UNC5H1, UNC5H2 and UNC5H3). Unlike chick netrin-1, however, murine netrin-3 binds to DCC with lower affinity than to the other four receptors. Consistent with this finding, although murine netrin-3 can mimic the outgrowth-promoting activity of netrin-1 on commissural axons, it has lower specific activity than netrin-1. Thus, like netrin-1, netrin-3 may also function in axon guidance during development but may function predominantly in the development of the peripheral nervous system and may act primarily through netrin receptors other than DCC.

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PubMed1997

Turning of retinal growth cones in a netrin-1 gradient mediated by the netrin receptor DCC.

Netrin-1 promotes outgrowth of axons in vitro through the receptor Deleted in Colorectal Cancer (DCC) and elicits turning of axons within embryonic explants when presented as a point source. It is not known whether netrin-1 alone can elicit turning nor whether DCC mediates the turning response. We show that Xenopus retinal ganglion cell growth cones orient rapidly toward a pipette ejecting netrin-1, an effect blocked by antibodies to DCC. In vitro, netrin-1 induces a complex growth cone morphology reminiscent of that at the optic nerve head, a site of netrin-1 expression in vivo. These results demonstrate that netrin-1 can function alone to induce turning, implicate DCC in this response, and support the idea that netrin-1 contributes to steering axons out of the retina.

Amino Acid Sequence↗

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.

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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.

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PubMed2000

The Drosophila Netrin receptor Frazzled guides axons by controlling Netrin distribution.

Netrin is a secreted protein that can act as a chemotropic axon guidance cue. Two classes of Netrin receptor, DCC and UNC-5 (refs 6-9), are required for axon guidance and are thought to mediate Netrin signals in growth cones through their cytoplasmic domains. However, in the guidance of Drosophila photoreceptor axons, the DCC orthologue Frazzled is required not in the photoreceptor neurons but instead in their targets, indicating that Frazzled also has a non-cell-autonomous function. Here we show that Frazzled can capture Netrin and 'present' it for recognition by other receptors. Moreover, Frazzled itself is actively localized within the axon through its cytoplasmic domain, and thereby rearranges Netrin protein into a spatial pattern completely different from the pattern of Netrin gene expression. Frazzled-dependent guidance of one pioneer neuron in the central nervous system can be accounted for solely on the basis of this ability of Frazzled to control Netrin distribution, and not by Frazzled signalling. We propose a model of patterning mechanism in which a receptor rearranges secreted ligand molecules, thereby creating positional information for other receptors.

Amino Acid Sequence↗

PubMed2006

Motor axon guidance of the mammalian trochlear and phrenic nerves: dependence on the netrin receptor Unc5c and modifier loci.

Netrin signaling is important to guide migrating neurons and axons in many systems. Experiments with vertebrate CNS explants suggested netrin is bifunctional, attracting some axons and repelling others. Netrin1-expressing cells attracted spinal commissural axons and repelled trochlear cranial nerve axons in these experiments. Subsequent genetic studies demonstrated that multiple axon types, including those of the spinal commissural neurons, are attracted to netrin in vivo; however, an in vivo role for netrin signaling in trochlear nerve repulsion has not been observed. Here, we demonstrate that mice with a null mutation in the netrin receptor Unc5c on the inbred C57BL/6J (B6) genetic background have ventral/ipsilateral trochlear nerve misprojections. These misprojections are attenuated on a hybrid B6 x SJL background. In addition, B6.Unc5c(-/-) mice die as neonates of apparent respiratory distress and have incomplete phrenic nerve innervation of the diaphragm muscle. Neither the trochlear nerve misprojections nor the phrenic nerve phenotype was observed in B6 embryos lacking the netrin receptors DCC or Neogenin1, or the ligand netrin1, indicating these signaling molecules are dispensable for guidance of these axons. Like the trochlear nerve, the phrenic nerve phenotype is modified in a B6 x SJL hybrid background. To identify these modifier loci, we performed genome scans of the hybrid Unc5c(-/-) mice and found a major SJL-derived suppressor locus on Chromosome 17. Our results provide the first evidence that genes involved in netrin signaling are necessary for proper mammalian spinal motor axon development and trochlear axon guidance. In addition, they demonstrate the importance of modifier genes in vertebrate axonal guidance.

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PubMed2006

Positioned to inhibit: netrin-1 and netrin receptor expression after spinal cord injury.

Netrin-1 regulates axon extension during embryonic development and is expressed by neurons and myelinating oligodendrocytes in the adult CNS. To investigate the potential role of netrin-1 after spinal cord injury, we examined the expression of netrin-1 and netrin receptors after sagittal myelotomy in adult rats. This lesion targets spinal commissural projections, which respond to netrin-1 during development. Netrin-1 mRNA and protein levels were dramatically reduced at the site of injury and reduced expression persisted for at least 7 months. Neither netrin-1 protein nor mRNA was associated with the glial scar, but netrin-1 was expressed by neurons and oligodendrocytes immediately adjacent to the lesion. The post-injury distribution detected is similar to that reported for myelin-associated inhibitors of axon regeneration, such as Nogo, and is distinct from the distribution of inhibitors associated with a glial scar. DCC and UNC-5 homologue (UNC5H) expression also was reduced after injury. Although UNC5H levels recovered, DCC expression at the site of injury remained approximately 50% of pre-injury values at 7 months. Increased UNC5H immunoreactivity was associated with fibers in the superficial layers of the dorsal horn and in fibers located in white matter adjacent to the lesion. The dominant expression of UNC5H on axons and neurons in the spinal cord after injury and the persistent expression of netrin-1 by oligodendrocytes surrounding the lesion are consistent with the hypothesis that netrin-1 is a myelin-associated inhibitor of axonal regeneration after spinal cord injury.

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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.

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PubMed2004

The Netrin receptor Neogenin is required for neural tube formation and somitogenesis in zebrafish.

The Netrin receptor Deleted in colon cancer (Dcc) has been shown to play a pivotal role in the guidance of nascent axons towards the ventral midline in the developing nervous systems of both vertebrates and invertebrates. In contrast, the function during embryogenesis of a second Dcc-like Netrin receptor Neogenin has not yet been defined. We used antisense morpholino oligonucleotides to knockdown Neogenin activity in zebrafish embryos and demonstrate that Neogenin plays an important role in neural tube formation and somitogenesis. In Neogenin knockdown embryos, cavitation within the neural rod failed to occur, producing a neural tube lacking a lumen. Somite formation was also defective, implicating Neogenin in the migration events underlying convergent extension during gastrulation. These observations suggest a role for Neogenin in determining cell polarity or migrational directionality of both neuroectodermal and mesodermal cells during early embryonic development.

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PubMed2004

Developmental shift in expression of netrin receptors in the rat spinal cord: predominance of UNC-5 homologues in adulthood.

Netrins are a family of secreted proteins required for normal neural development. Netrin-1 is expressed at similar levels in the adult rat spinal cord and the embryonic CNS, suggesting that it contributes to adult CNS function. Here we show that the netrin receptors dcc, neogenin, unc5h1, unc5h2, and unc5h3 are also expressed in the adult rat spinal cord. Lower levels of DCC and neogenin were detected in the adult relative to the embryonic CNS. Conversely, the adult spinal cord contains increased levels of UNC-5 homologues in comparison with the embryo. Multiple mRNA transcripts detected by Northern blot analysis suggested that netrin receptors might be encoded by alternatively spliced mRNAs. We have identified a novel alternatively spliced mRNA encoding UNC5H1, UNC5H1(Delta)TSP1, which lacks the first of the two extracellular thrombospondin domains. This novel splice variant is the major transcript detected in the early embryonic CNS, although both splice variants are expressed in the adult. Previously identified alternatively spliced mRNAs encoding DCC and neogenin were also detected. Dcc, neogenin, unc5h1, unc5h2, and unc5h3 are expressed by subsets of neurons. Robust expression of unc5h2 was found in glia. These findings suggest that unc-5 homologues constitute a major mode of netrin-1 signal transduction in the adult spinal cord and may be involved in phenomena analogous to axon repulsion, such as inhibiting process extension and collateral sprouting.

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PubMed1997

Netrin and netrin receptor expression in the embryonic mammalian nervous system suggests roles in retinal, striatal, nigral, and cerebellar development.

The netrins are laminin-like axon guidance molecules that are conserved among Caenorhabditis elegans, Drosophila, and vertebrates and that have chemoattractive and chemorepellant properties. To study the possible actions of this gene family in the developing and adult mammalian nervous systems, we have cloned a partial cDNA which corresponds to a region conserved among chick netrin-1, netrin-2, and unc-6 and studied its expression and that of a netrin receptor, dcc, the deleted in colorectal cancer gene, in the developing and adult rat CNS. The localization of cells expressing netrin or dcc suggests that these genes, in addition to their actions in defining the ventral midline, may act in controlling retinal ganglion cell axon guidance in the optic nerve, cell migration in the developing cerebellum and olfactory epithelium, and development and maintenance of connections to the substantia nigra and corpus striatum.

Aging↗

PubMed2005

Planarian homologs of netrin and netrin receptor are required for proper regeneration of the central nervous system and the maintenance of nervous system architecture.

Conserved axon guidance mechanisms are essential for proper wiring of the nervous system during embryogenesis; however, the functions of these cues in adults and during regeneration remain poorly understood. Because freshwater planarians can regenerate a functional central nervous system (CNS) from almost any portion of their body, they are useful models in which to study the roles of guidance cues during neural regeneration. Here, we characterize two netrin homologs and one netrin receptor family member from Schmidtea mediterranea. RNAi analyses indicate that Smed-netR (netrin receptor) and Smed-netrin2 are required for proper CNS regeneration and that Smed-netR may mediate the response to Smed-netrin2. Remarkably, Smed-netR and Smed-netrin2 are also required in intact planarians to maintain the proper patterning of the CNS. These results suggest a crucial role for guidance cues, not only in CNS regeneration but also in maintenance of neural architecture.

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PubMed2004

The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system.

Blood vessels and nerves are complex, branched structures that share a high degree of anatomical similarity. Guidance of vessels and nerves has to be exquisitely regulated to ensure proper wiring of both systems. Several regulators of axon guidance have been identified and some of these are also expressed in endothelial cells; however, the extent to which their guidance functions are conserved in the vascular system is still incompletely understood. We show here that the repulsive netrin receptor UNC5B is expressed by endothelial tip cells of the vascular system. Disruption of the Unc5b gene in mice, or of Unc5b or netrin-1a in zebrafish, leads to aberrant extension of endothelial tip cell filopodia, excessive vessel branching and abnormal navigation. Netrin-1 causes endothelial filopodial retraction, but only when UNC5B is present. Thus, UNC5B functions as a repulsive netrin receptor in endothelial cells controlling morphogenesis of the vascular system.

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PubMed2001

Expression patterns of the netrin receptor UNC5H1 among developing motor neurons in the embryonic rat hindbrain.

The axon guidance molecule netrin-1 has been implicated in the midline repulsion of developing cranial motor axons. We have examined expression patterns of the netrin receptors UNC5H1 and DCC in embryonic rat hindbrains, in combination with labelling of developing motor neurons. We found that UNC5H1 expression colocalised with a number of cranial motor neuron subpopulations from embryonic day 11 (E11) to E14, while DCC was expressed by motor neurons at E12.

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PubMed2005

Netrin receptor deficient mice exhibit functional reorganization of dopaminergic systems and do not sensitize to amphetamine.

Netrins are guidance cues that play a fundamental role in organizing the developing brain. The netrin receptor, DCC (deleted in colorectal cancer), is highly expressed by dopaminergic (DA) neurons. DCC may therefore participate in the organization of DA circuitry during development and also influence DA function in the adult. Here we show that adult dcc heterozygous mice exhibit a blunted behavioral response to the indirect DA agonist amphetamine and do not develop sensitization to its effects when treated repeatedly. These behavioral alterations are associated with profound changes in DA function. In the medial prefrontal cortex, dcc heterozygotes exhibit increased tyrosine hydroxylase (TH) protein levels and dramatic increases in basal concentrations of DA and DA metabolites. In contrast, in the nucleus accumbens, dcc heterozygotes show no changes in either TH or DA levels, but exhibit decreased concentrations of DA metabolites, suggesting reduced DA activity. In addition, dcc heterozygous mice exhibit a small, but significant reduction in total number of TH-positive neurons in midbrain DA cell body regions. These results demonstrate for the first time that alterations in dcc expression lead to selective changes in DA function and, in turn, to differences in DA-related behaviors in adulthood. These findings raise the possibility that changes in dcc function early in life are implicated in the development of DA dysregulation observed in certain psychiatric disorders, such as schizophrenia, or following chronic use of drugs of abuse.

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PubMed1999

The netrin receptor frazzled is required in the target for establishment of retinal projections in the Drosophila visual system.

Retinal axons in Drosophila make precise topographic connections with their target cells in the optic lobe. Here we investigate the role of the Netrins and their receptor Frazzled in the establishment of retinal projections. We find that the Netrins, although expressed in the target, are not required for retinal projections. Surprisingly, Frazzled, found on both retinal fibers and target cells, is required in the target for attracting retinal fibers, while playing at best a redundant role in the retinal fibers themselves; this finding demonstrates that target attraction is necessary for topographic map formation. Finally, we show that Frazzled is not required for the differentiation of cells in the target. Our data suggest that Frazzled does not function as a Netrin receptor in attracting retinal fibers to the target; nor does it seem to act as a homotypic cell adhesion molecule. We favor the possibility that Frazzled in the target interacts with a component on the surface of retinal fibers, possibly another Netrin receptor.

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