Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neonatal ventral hippocampal (nVH) lesions in rats, which model certain features of schizophrenia, alter dopamine (DA)-mediated behaviors in adulthood. The precise mechanisms underlying these effects remain elusive; however, neuronal reorganization within the medial prefrontal cortex (mPFC) has been suggested. Netrins are developmental cues that organize brain wiring, including the mesocorticolimbic DA circuitry. We showed recently that the netrin-1 receptors DCC and UNC5H are highly expressed by DA neurons and that variation in DCC levels during development lead to profound changes in mesocorticolimbic DA function and behavior in adulthood. We hypothesized that changes in netrin-1 receptor function could be one of the mechanisms producing enduring changes in DA function in nVH-lesioned animals. To begin to explore this idea, we examined the effects of nVH lesions on DCC and UNC5H expression in brain regions receiving robust DA innervation; the mPFC, striatum, and nucleus accumbens (NAcc) at three developmental time points; 3 days after lesion, before puberty and during early adulthood. Expression was also examined in the cerebellar simple lobule; a brain region deprived of DA innervation. Neonatal VH lesions produced dynamic changes in DCC expression in the mPFC and NAcc. The direction and magnitude of these changes depended on the developmental age and brain region examined and were specific to regions receiving DA innervation. Although further studies are required to understand the functional significance of these changes, these results raise the interesting possibility that nVH lesions, and perinatal insults in general, may exert their neuronal reorganizational effects by modulating netrin-1 function.
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PMID:Altered netrin-1 receptor expression in dopamine terminal regions following neonatal ventral hippocampal lesions in the rat. 1893 28

Netrin-1 attracts or repels growing axons during development. The UNC5 receptors mediate the repulsive response, either alone or in complex with DCC receptors. The signaling mechanisms activated by UNC5 are poorly understood. Here, we examined the role of Rho GTPases in UNC5a signaling. We found that UNC5a induced neurite outgrowth in N1E-115 neuroblastoma cells in a netrin-1- and Rac1-dependent manner. UNC5a lacking its cytoplasmic tail also mediated this effect. In fibroblasts, UNC5a was able to activate RhoA and to a lower extent Rac1 and Cdc42 in response to netrin-1. Using Fluorescence Resonance Energy Transfer (FRET) intermolecular probes, we visualized the spatial and temporal activation of Rac1, Cdc42 and RhoA in live N1E-115 cells expressing UNC5a during neurite outgrowth. We found that Rac1 but not Cdc42 was transiently activated at the leading edge of the cell during neurite initiation. However, at later times when well-developed neurites were formed, active RhoA was found in the cell body and at the base of the neuronal leading process in UNC5a-expressing cells. Together, these findings demonstrate that the netrin-1 receptor UNC5a is able to induce neurite outgrowth and to differentially activate RhoA and Rac1 during neurite extension in a spatial and temporal manner.
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PMID:Spatial and temporal activation of the small GTPases RhoA and Rac1 by the netrin-1 receptor UNC5a during neurite outgrowth. 1975 50

Netrins are a family of proteins that mediate axonal guidance in the central nervous system (CNS). In addition to the CNS, netrins are involved in cell adhesion, motility, proliferation, differentiation, and survival. Because these processes occur in the placenta, we raised the question of whether netrin-1 is expressed by placental cells during development. In the present study, we analyzed the spatial and temporal distribution of netrin-1 and its two receptors, DCC (deleted in colorectal cancer) and UNC5B (uncoordinated-5 homolog) in human placenta using RT-PCR, Western blotting, and immunohistochemistry analysis. We demonstrated the presence of the proteins and transcripts of netrin-1 and its receptors in placenta and cytotrophoblasts. Furthermore, using immunohistochemistry, we localized endogenous netrin-1 protein staining to villous and extravillous cytotrophoblasts, and secreted netrin-1 outside the syncytiotrophoblasts. The DCC receptor was localized to syncytiotrophoblasts and invasive extravillous cytotrophoblasts during the first trimester and at term. On the other hand, the UNC5B receptor was localized to villous and extravillous cytotrophoblasts proximal to anchoring areas during the first trimester. At term, UNC5B was observed in decidual cells and weakly in extravillous cells. The discrete pattern of netrin-1 and netrin-1 receptor distribution suggested that netrin-1 protein functions might vary with its localization in the placenta and probably with time of gestation.
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PMID:Characterization and expression of netrin-1 and its receptors UNC5B and DCC in human placenta. 1982 74

Proper axonal targeting is fundamental to the establishment of functional neural circuits. The hippocampal mossy fibres normally project towards the CA3 region. In the hippocampi of patients with temporal lobe epilepsy and related animal models, however, mossy fibres project towards the molecular layer and produce the hyperexcitable recurrent networks. The cellular and molecular mechanisms underlying this aberrant axonal targeting, known as mossy fibre sprouting, remain unclear. Netrin-1 attracts or repels axons depending on the composition of its attraction-mediating receptor, deleted in colorectal cancer, and its repulsion-mediating receptor, uncoordinated-5, on the growth cone; but the roles of netrin-1-dependent guidance in pathological conditions are largely unknown. In this study, we examined the role of netrin-1 and its receptors in mossy fibre guidance and report that enhanced neuronal activity changes netrin-1-mediated cell targeting by the axons under hyperexcitable conditions. Netrin-1 antibody or Dcc ribonucleic acid interference attenuated mossy fibre growth towards CA3 in slice overlay assays. The axons were repelled from CA3 and ultimately innervated the molecular layer when hyperactivity was pharmacologically introduced. We first hypothesized that a reduction in netrin-1 expression in CA3 underlies the phenomenon, but found that its expression was increased. We then examined two possible activity-dependent changes in netrin-1 receptor expression: a reduction in the deleted in colorectal cancer receptor and induction of uncoordinated-5 receptor. Hyperactivity did not affect the surface expression of the deleted in colorectal cancer receptor on the growth cone, but it increased that of uncoordinated-5A, which was suppressed by blocking cyclic adenosine monophosphate signalling. In addition, Dcc knockdown did not affect hyperactivity-induced mossy fibre sprouting in the slice cultures, whereas Unc5a knockdown rescued the mistargeting. Thus, netrin-1 appears to attract mossy fibres via the deleted in colorectal cancer receptor, while it repels them via cyclic adenosine monophosphate-induced uncoordinated-5A under hyperexcitable conditions, resulting in mossy fibre sprouting.
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PMID:The ratio of 'deleted in colorectal cancer' to 'uncoordinated-5A' netrin-1 receptors on the growth cone regulates mossy fibre directionality. 1985 80

Fundamental to neural organization during development, the netrin-1 guidance cue and its receptor, deleted in colorectal cancer (DCC), continue to be expressed in the adult brain. We have shown recently that adult dcc heterozygous mice do not develop sensitization to the stimulant drug of abuse amphetamine (AMPH) and that repeated exposure to AMPH upregulates DCC expression in adult rats. This upregulation is selective to the ventral tegmental area (VTA), a site critical for the initiation of behavioral plasticity induced by stimulant drugs, and is glutamate-dependent. Here we demonstrate that the lack of AMPH-induced sensitization in dcc heterozygotes is associated with a failure of AMPH to upregulate DCC receptor expression in the VTA. Further, we show that, in wild-type mice, repeated AMPH induces increases in VTA expression of the dendritic spine-associated protein, spinophilin. Significantly, however, this effect is not observed in dcc heterozygotes. In parallel experiments conducted in adult rats, we show that VTA DCC receptor activation, at the time of AMPH pretreatment, is critical for sensitization to AMPH. Together, these results demonstrate that the DCC netrin-1 receptor, a protein traditionally known for its role in organizing brain development, plays a critical function in adult brain plasticity, possibly via orchestration of neuronal circuitry reorganization. We propose VTA DCC receptor signaling as a novel mechanism in the series of glutamate-dependent cellular processes that lead to enduring plasticity by drugs of abuse.
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PMID:Netrin-1 receptor in the ventral tegmental area is required for sensitization to amphetamine. 2034 16

Puberty is a critical period in mesocorticolimbic dopamine (DA) system development, particularly for the medial prefrontal cortex (mPFC) projection which achieves maturity in early adulthood. The guidance cue netrin-1 organizes neuronal networks by attracting or repelling cellular processes through DCC (deleted in colorectal cancer) and UNC-5 homologue (UNC5H) receptors, respectively. We have shown that variations in netrin-1 receptor levels lead to selective reorganization of mPFC DA circuitry, and changes in DA-related behaviors, in transgenic mice and in rats. Significantly, these effects are only observed after puberty, suggesting that netrin-1 mediated effects on DA systems vary across development. Here we report on the normal expression of DCC and UNC5H in the ventral tegmental area (VTA) by DA neurons from embryonic life to adulthood, in both mice and rats. We show a dramatic and enduring pubertal change in the ratio of DCC:UNC5H receptors, reflecting a shift toward predominant UNC5H function. This shift in DCC:UNC5H ratio coincides with the pubertal emergence of UNC5H expression by VTA DA neurons. Although the distribution of DCC and UNC5H by VTA DA neurons changes during puberty, the pattern of netrin-1 immunoreactivity in these cells does not. Together, our findings suggest that DCC:UNC5H ratios in DA neurons at critical periods may have important consequences for the organization and function of mesocorticolimbic DA systems.
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PMID:Peri-pubertal emergence of UNC-5 homologue expression by dopamine neurons in rodents. 2062 9

Changes in mesocorticolimbic dopamine (DA) neurons and their target cells can be induced throughout life and are important determinants of individual differences in susceptibility to psychopathology. The goal of my research is to gain insight into the nature of the cellularand molecular mechanism underlying the selective plasticity of mesocorticolimbic DA neurons. Here, I review work showing that the guidance cue netrin-1 is implicated in the organization, plasticity and function of mesocorticolimbic DA neurons in rodents. Developmental variations in netrin-1 receptor function result in selective reorganization of medial prefrontal DA circuitry during adolescence and in an adult phenotype protected against schizophrenia-like dopaminergic and behavioural abnormalities. Furthermore, in adulthood, expression of netrin-1 receptors is upregulated by repeated exposure to stimulant drugs of abuse in DA somatodendritic regions and is necessary for drug-induced behavioural plasticity. I propose that risk factors associated with DA-related adult psychiatric disorders alter netrin-1 function.
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PMID:Role of netrin-1 in the organization and function of the mesocorticolimbic dopamine system. 2148 3

Inappropriate gene silencing and subsequent promiscuous activity define the transformation of many solid tumours including renal cell carcinoma (RCC). Here, we report that UNC5C, one of the Netrin-1 receptors, was frequently inactivated in RCC cell lines and primary tumours. UNC5C protein was expressed in the proximal convoluted tubules of the human kidney, the presumed origin of clear cell RCC (ccRCC) and papillary RCC (pRCC). Compared to paired adjacent non-malignant tissues, both UNC5C mRNA and protein expression were significantly down-regulated in RCC. Immunohistochemical analysis showed that UNC5C was inactivated in 94.3% of the samples and the loss of UNC5C occurred at the early stage of RCC. Methylation specific PCR showed that UNC5C promoter was methylated in two renal carcinoma cell lines. Pharmacologic demethylation alone or in combination with inhibition of deacetylation dramatically induced UNC5C expression. Furthermore, bisulfite genomic sequencing (BGS) confirmed that dense methylation existed in UNC5C promoter. In paired tumour samples, UNC5C methylation was observed in 12 out of 44 patients (27.3%). Moreover, we analysed the loss of heterozygosity (LOH) of UNC5C in renal cell carcinoma, the LOH was observed in 27 out of 44 patients (61.4%). Finally, restoration of UNC5C expression suppressed the colony formation of renal carcinoma cells. In addition, UNC5C inhibited tumour cell proliferation, migration and enhanced chemosensitivity to cisplatin and etoposide. Therefore, UNC5C acts as a tumour suppressor in RCC and is down-regulated in RCC. Loss of heterozygosity and DNA methylation contribute to the inactivation of UNC5C in renal cell carcinoma.
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PMID:Genetic and epigenetic control of UNC5C expression in human renal cell carcinoma. 2160 Jul 61

Netrins are guidance cues involved in neural connectivity. We have shown that the netrin-1 receptor DCC (deleted in colorectal cancer) is involved in the functional organization of the mesocorticolimbic dopamine (DA) system. Adult mice with a heterozygous loss-of-function mutation in dcc exhibit changes in indexes of DA function, including DA-related behaviors. These phenotypes are only observed after puberty, a critical period in the maturation of the mesocortical DA projection. Here, we examined whether dcc heterozygous mice exhibit structural changes in medial prefrontal cortex (mPFC) DA synaptic connectivity, before and after puberty. Stereological counts of tyrosine-hydroxylase (TH)-positive varicosities were increased in the cingulate 1 and prelimbic regions of the pregenual mPFC. dcc heterozygous mice also exhibited alterations in the size, complexity, and dendritic spine density of mPFC layer V pyramidal neuron basilar dendritic arbors. Remarkably, these presynaptic and postsynaptic partner phenotypes were not observed in juvenile mice, suggesting that DCC selectively influences the extensive branching and synaptic differentiation that occurs in the maturing mPFC DA circuit at puberty. Immunolabeling experiments in wild-type mice demonstrated that DCC is segregated to TH-positive fibers innervating the nucleus accumbens, with only scarce DCC labeling in mPFC TH-positive fibers. Netrin had an inverted target expression pattern. Thus, DCC-mediated netrin-1 signaling may influence the formation/maintenance of mesocorticolimbic DA topography. In support of this, we report that dcc heterozygous mice exhibit a twofold increase in the density of mPFC DCC/TH-positive varicosities. Our results implicate DCC-mediated netrin-1 signaling in the establishment of mPFC DA circuitry during puberty.
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PMID:The netrin receptor DCC is required in the pubertal organization of mesocortical dopamine circuitry. 2165 43

The role of deleted in colorectal carcinoma (DCC) as a tumour suppressor has been a matter of debate for the past 15 years. DCC gene expression is lost or markedly reduced in the majority of advanced colorectal cancers and, by functioning as a dependence receptor, DCC has been shown to induce apoptosis unless engaged by its ligand, netrin-1 (ref. 2). However, so far no animal model has supported the view that the DCC loss-of-function is causally implicated as predisposing to aggressive cancer development. To investigate the role of DCC-induced apoptosis in the control of tumour progression, here we created a mouse model in which the pro-apoptotic activity of DCC is genetically silenced. Although the loss of DCC-induced apoptosis in this mouse model is not associated with a major disorganization of the intestines, it leads to spontaneous intestinal neoplasia at a relatively low frequency. Loss of DCC-induced apoptosis is also associated with an increase in the number and aggressiveness of intestinal tumours in a predisposing APC mutant context, resulting in the development of highly invasive adenocarcinomas. These results demonstrate that DCC functions as a tumour suppressor via its ability to trigger tumour cell apoptosis.
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PMID:DCC constrains tumour progression via its dependence receptor activity. 2215 21


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