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PubMed2001

Netrin-1 acts as a survival factor via its receptors UNC5H and DCC.

The membrane receptors DCC and UNC5H have been shown to be crucial for axon guidance and neuronal migration by acting as receptors for netrin-1. DCC has also been proposed as a dependence receptor inducing apoptosis in cells that are beyond netrin-1 availability. Here we show that 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, we demonstrate that 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. Finally, we present evidence 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.

Animals↗
PubMed2006

Axonal growth regulation of fetal and embryonic stem cell-derived dopaminergic neurons by Netrin-1 and Slits.

The physical restoration of dopamine circuits damaged or lost in Parkinson disease by implanting embryonic stem (ES)-derived cells may become a treatment. It is critical to understand responses of ES-derived dopamine (DA) neurons to guidance signals that determine axonal path and targeting. Using a collagen gel culture system, we examined effects of secreted molecules Netrin-1 and Slits on neurite outgrowth of fetal DA neurons and murine ES-differentiated DA neurons. We have previously shown that fetal DA neurons express DCC and Robo1/2 receptors and that Netrin-1 and Slit2 function as an attractant and a repellent for DA neurite outgrowth. In the present study, we observe that both Slit1 and Slit3 repel and inhibit neurite growth of fetal DA neurons. Here, we also demonstrate that ES-differentiated neurons including DA neurons express the Netrin receptor DCC and Slit receptor Robo proteins. In the gel culture system of ES cells, Netrin-1 promoted neurite outgrowth mediated by DCC receptor, and Slit1 and Slit3 were inhibitory for neurite outgrowth through Robo receptors. Slit2 appeared to exert inhibitory as well as repulsive effects in the coculture assay. However, unlike fetal DA neurites, no directed neurite outgrowth was observed in the cocultures of ES-derived DA neurons with Netrin-1-, Slit1-, and Slit3-producing cells. The findings suggest that ES-derived DA neurons generated by current protocols can respond to guidance cues in vitro in a similar manner to fetal cells but also exhibit distinct responses. This may result from developmental differences generated by present in vitro methods of cell patterning or conditioning during ES cell differentiation.

Animals↗
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↗
PubMed2004

Netrin-1 is crucial for the establishment of the dorsal column-medial lemniscal system.

The dorsal column-medial lemniscal system is a significant sensory pathway that mediates touch and limb position sense. In this system, axons from the second-order neurons in the dorsal column nuclei form the internal arcuate fibers, cross the ventral midline (floor plate) within the medulla oblongata, and then project to the thalamus as the medial lemniscus. Here we demonstrate that Netrin-1, which is secreted from the floor plate in the medulla oblongata, is indispensable to the formation of the dorsal column-medial lemniscal system. Axons from the dorsal column nuclei cross the midline at around embryonic day 11 in mice. Concurrently, Netrin-1 mRNA and its receptor DCC (deleted in colorectal cancer) were expressed in the floor plate and commissural axons there, respectively. In our explant culture experiments, the floor plates of the embryonic 11-day-old mutant Netrin-1 homozygous mice did not attract axons from the dorsal column nuclei of ICR mice, while those from the wild type littermates did. Moreover, we observed that although the dorsal column nuclei developed in situ in mutant mice, their axons were not attracted toward the floor plate: they did not cross midline and remained ipsilaterally, without forming the internal arcuate fibers, in embryonic 17-day-old mutant Netrin-1 homozygous mice.

Afferent Pathways↗
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↗
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↗
PubMed2006

Netrin/DCC signaling controls contralateral dendrites of octavolateralis efferent neurons.

The guidance molecule Netrin and its receptor DCC (deleted in colorectal cancer) attract commissural axons toward the midline en route to their final destination. To test whether these molecules can also guide dendrites, we studied the contralateral dendrites of zebrafish octavolateralis efferent (OLe) neurons, which are unusual in that they navigate toward and cross the midline. We found that, at the time of dendrite outgrowth, OLe neurons express dcc, and the hindbrain midline expresses netrin1. Knocking down dcc or netrin1 function by injecting antisense morpholino oligonucleotides prevented OLe contralateral dendrites from crossing the midline, showing that dcc and netrin1 are necessary for dendrite guidance or formation. Furthermore, by transplanting cells from dcc morphants into wild-type embryos and vice versa, we demonstrated that dcc acts cell autonomously in OLe dendrites. This work is the first evidence that Netrin/DCC signaling acts in dendrites in a vertebrate system.

Animals↗
PubMed1999

Retracted: A ligand-gated association between cytoplasmic domains of UNC5 and DCC family receptors converts netrin-induced growth cone attraction to repulsion.

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, we studied the attractive responses of Xenopus spinal axons to netrin-1, which are mediated by DCC. We show that attraction is converted to repulsion by expression of UNC5 proteins in these cells, that this repulsion requires DCC function, that the UNC5 cytoplasmic domain is sufficient to effect the conversion, and that 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. We provide evidence 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.

Amino Acid Sequence↗
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↗
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↗
PubMed2003

Netrin-1 is a chemorepellent for oligodendrocyte precursor cells in the embryonic spinal cord.

Netrin-1, secreted by floor plate cells, orients axon extension in relation to the ventral midline of the embryonic spinal cord. Oligodendrocyte precursor (OP) cells are born close to the ventral midline and migrate away from the floor plate. Here we show that OP cells, identified by expression of the platelet-derived growth factor alpha receptor, express the netrin receptors dcc and unc5h1 but do not express netrin-1. Using a microchemotaxis assay, we demonstrate that migrating OPs are repelled by a gradient of netrin-1 in vitro. Furthermore, application of netrin-1 to OPs in vitro triggers retraction of OP processes. In the absence of netrin-1 or Deleted in Colorectal Cancer (DCC) function in vivo, fewer OP cells migrate from the ventral to the dorsal embryonic spinal cord, consistent with netrin-1 acting as a repellent. In addition to their role regulating cell movement, DCC and UNC-5 homologs have been suggested to function as proapoptotic dependence receptors, triggering cell death in the absence of netrin-1. In contrast, we report no evidence of increased OP cell death in vivo or in vitro in the absence of either netrin-1 or DCC. These findings indicate that netrin-1 is a repellent cue for migrating OPs in the embryonic spinal cord.

Animals↗
PubMed1999

Altered midline axon pathways and ectopic neurons in the developing hypothalamus of netrin-1- and DCC-deficient mice.

Optic nerve formation in mouse involves interactions between netrin-1 at the optic disk and the netrin-1 receptor DCC (deleted in colorectal cancer) expressed on retinal ganglion cell (RGC) axons. Deficiency in either protein causes RGC pathfinding defects at the disk leading to optic nerve hypoplasia (). Here we show that further along the visual pathway, RGC axons in netrin-1- or DCC-deficient mice grow in unusually angular trajectories within the ventral hypothalamus. In heterozygous Sey(neu) mice that also have a small optic nerve, RGC axon trajectories appear normal, indicating that the altered RGC axon trajectories in netrin-1 and DCC mutants are not secondarily caused by optic nerve hypoplasia. Intrinsic hypothalamic patterning is also affected in netrin-1 and DCC mutants, including a severe reduction in the posterior axon projections of gonadotropin-releasing hormone neurons. In addition to axon pathway defects, antidiuretic hormone and oxytocin neurons are found ectopically in the ventromedial hypothalamus, apparently no longer confined to the supraoptic nucleus in mutants. In summary, netrin-1 and DCC, presumably via direct interactions, govern both axon pathway formation and neuronal position during hypothalamic development, and loss of netrin-1 or DCC function affects both visual and neuroendocrine systems. Netrin protein localization also indicates that unlike in more caudal CNS, guidance about the hypothalamic ventral midline does not require midline expression of netrin.

Adrenocorticotropic Hormone↗
PubMed2004

Netrin-1 and its receptors in tumorigenesis.

Netrin-1 and its receptors DCC (deleted in colorectal cancer) and the UNC5 orthologues (human UNC5A-D and rodent UNC5H1-4) define a new mechanism for both the positive (induction) and negative (suppression) regulation of apoptosis. Accumulating evidence implies that for human cancers, this positive signalling pathway is frequently inactivated. Surprisingly, binding of netrin-1 to its receptors inhibits tumour suppressor p53-dependent apoptosis, and p53 is directly involved in transcriptional regulation of netrin-1 and its receptors. So, the netrin-1 receptor pathways probably play an important part in tumorigenesis.

Axons↗
PubMed2002

The netrin 1 receptors Unc5h3 and Dcc are necessary at multiple choice points for the guidance of corticospinal tract axons.

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. We demonstrate that 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, we show that corticospinal tract fibers respond differently to loss of UNC5H3. In addition, we observe corticospinal tract defects 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.

Animals↗
PubMed1994

Steroid receptors in carcinoma of the breast. Results of immunocytochemical and biochemical determination and their effects on short-term prognosis.

A group of 241 nonpretreated breast carcinomas was studied for estrogen receptor (ER) and progesterone receptor (PR) content by both immunocytochemistry (ICC) and biochemical analysis (dextran-coated charcoal [DCC]). While the tumors were judged to be ER positive in 67.6% and PR positive in 65.6% by ICC, DCC analysis showed positive results in 77.6% for both ER and PR. There was only a moderate correlation between the semiquantitative results of ER and PR ICC and the corresponding values for DCC receptor determination. Among tumors shown to be steroid receptor positive by ICC, a majority showed a wide spectrum of staining intensity, from negative to intensely positive (type C staining pattern, ER 87.7%, PR 73.4%). Less frequently, carcinomas showing uniform, intense staining of all epithelial tumor cells were observed (type A staining pattern, ER 11.7%, PR 18.4%). Finally, only very few tumors had both clearly negative and distinctly positive cells (type B staining pattern, ER 0.6%, PR 8.2%). On analyzing the relationship between the expression of steroid receptors (ICC and DCC) and the prognostic factors axillary node status, tumor size, tumor histology, grade and patient age, only a significant correlation between patient age and ER (ICC, r = .46; DCC, r = .43), a weakly significant negative correlation between node involvement and ER, and a weakly significant negative correlation between tumor grade and ER (ICC only) as well as between tumor grade and PR were found. Among all patients, the recurrence-free interval was significantly longer in patients with ER- or PR-positive carcinomas (ICC and DCC).(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
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↗
PubMed2006

Localization of Neogenin protein during morphogenesis in the mouse embryo.

Neogenin, a close relative of the axon guidance receptor DCC, has been shown to be a receptor for members of the Netrin and Repulsive Guidance Molecule families. Recent studies have begun to uncover a role for Neogenin in organogenesis. Here we examine the localization of Neogenin protein in the developing mouse embryo (embryonic day 14.5) when organogenesis is progressing rapidly. We observe that Neogenin protein is restricted to distinct tissue layers within a given organ. In some embryonic epithelia such as the gut and pancreas, Neogenin protein is predominantly polarized to the basal surfaces of the epithelial cells. In contrast, Neogenin is restricted to mesenchymal cells within the lung and kidney. Neogenin is also seen in differentiating skeletal muscle and condensing cartilage throughout the embryo, and in the trigeminal and dorsal root ganglia of the peripheral nervous system. This study supports the emerging role for Neogenin as a key receptor in the establishment of the morphological architecture in many developing organ systems.

Animals↗
PubMed2005

Netrin-1: when a neuronal guidance cue turns out to be a regulator of tumorigenesis.

Netrin-1 has been shown to play a crucial role in neuronal navigation during nervous system development mainly through its interaction with its receptors DCC and UNC5H. However, initially the DCC (deleted in colorectal cancer) gene was proposed as a putative tumor suppressor gene. It was then difficult to reconcile the two activities of DCC until the observation that DCC belongs to an emerging family of receptors named dependence receptors. Such receptors share the property of inducing apoptosis in the absence of ligand, hence creating a cellular state of dependence on the ligand. Thus, netrin-1 may not only be a chemotropic factor for neurons but also a survival factor. We will review here the identification of netrin-1 and its receptors, the signaling pathways initiated in the presence or absence of netrin-1. We will suggest some possible roles of netrin-1 in nervous system development, neovascularisation, adhesion and tumorigenesis.

Animals↗