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At least 19 recordsLinked to original sources
PubMed1999

Vertebrate slit, a secreted ligand for the transmembrane protein roundabout, is a repellent for olfactory bulb axons.

The olfactory bulb plays a central role in olfactory information processing through its connections with both peripheral and cortical structures. Axons projecting from the olfactory bulb to the telencephalon are guided by a repulsive activity in the septum. The molecular nature of the repellent is not known. We report here the isolation of vertebrate homologs of the Drosophila slit gene and show that Slit protein binds to the transmembrane protein Roundabout (Robo). Slit is expressed in the septum whereas Robo is expressed in the olfactory bulb. Functionally, Slit acts as a chemorepellent for olfactory bulb axons. These results establish a ligand-receptor relationship between two molecules important for neural development, suggest a role for Slit in olfactory bulb axon guidance, and reveal the existence of a new family of axon guidance molecules.

Animals↗
PubMed2005

Serum levels of Magic Roundabout protein in patients with advanced non-small cell lung cancer (NSCLC).

BACKGROUND: Magic Roundabout (MR; ROBO 4) is a recently discovered gene which encodes a protein that derived its name form the structural homology with the roundabout family of genes. Genes of the roundabout family comprise neuronal-specific cell surface receptors that are involved in axon guidance. MR in contrast showed endothelial specificity in vitro and in vivo using immunohistochemistry and in situ hybridisation. The putative role of MR as an endothelial analogue of Roundabout in angiogenesis makes it an attractive target for anti-angiogenic cancer therapy. PATIENTS AND METHODS: Using specific antibodies against MR peptide, we screened pretreatment sera from 193 patients with advanced non-small cell lung cancer (NSCLC) for MR-protein levels. RESULTS: Patients with serum levels of MR-protein lower than median (E(450 nm) = 0.652) had a median survival of 41.0 weeks whereas those with a higher serum level had a considerably shorter median survival of 32.4 weeks (P = 0.05). The pretreatment serum level of MR-protein achieved no significance in a univariate Cox regression analysis. CONCLUSIONS: This is the first study to present clinical data that link MR expression with outcome in patients with NSCLC, whether the correlation of pretreatment serum levels of MR and survival can be attributed to MR dependent angiogenesis remains to be investigated.

Adult↗
PubMed2004

Motor-protein "roundabouts": microtubules moving on kinesin-coated tracks through engineered networks.

Nanotechnology promises to enhance the functionality and sensitivity of miniaturized analytical systems. For example, nanoscale transport systems, which are driven by molecular motors, permit the controlled movement of select cargo along predetermined paths. Such shuttle systems may enhance the detection efficiency of an analytical system or facilitate the controlled assembly of sophisticated nanostructures if transport can be coordinated through complex track networks. This study determines the feasibility of complex track networks using kinesin motor proteins to actively transport microtubule shuttles along micropatterned surfaces. In particular, we describe the performance of three basic structural motifs: (1) crossing junctions, (2) directional sorters, and (3) concentrators. We also designed track networks that successfully sort and collect microtubule shuttles, pointing the way towards lab-on-a-chip devices powered by active transport instead of pressure-driven or electroosmotic flow.

Animals↗
PubMed2002

Drosophila Nedd4, a ubiquitin ligase, is recruited by Commissureless to control cell surface levels of the roundabout receptor.

Crossing the midline produces changes in axons such that they are no longer attracted to the midline. In Drosophila, Roundabout reaches high levels on axons once they have crossed the midline, and this prohibits recrossing. Roundabout protein levels are regulated by Commissureless. We show that Commissureless binds to and is regulated by the ubiquitin ligase DNedd4. We further show that the ability of Commissureless to regulate Roundabout protein levels requires an intact DNedd4 binding site and ubiquitin acceptor sites within the Commissureless protein. The ability of Commissureless to regulate Robo in the embryo also requires a Commissureless/DNedd4 interaction. Our results show that changes in axonal sensitivity to external cues during pathfinding across the midline makes use of ubiquitin-dependent mechanisms to regulate transmembrane protein levels.

Animals↗
PubMed2000

In silico cloning of novel endothelial-specific genes.

The endothelium plays a pivotal role in many physiological and pathological processes and is known to be an exceptionally active transcriptional site. To advance our understanding of endothelial cell biology and to elucidate potential pharmaceutical targets, we developed a new database screening approach to permit identification of novel endothelial-specific genes. The UniGene gene index was screened using high stringency BLAST against a pool of endothelial expressed sequence tags (ESTs) and a pool of nonendothelial ESTs constructed from cell-type-specific dbEST libraries. UniGene clusters with matches in the endothelial pool and no matches in the nonendothelial pool were selected. The UniGene/EST approach was then combined with serial analysis of gene expression (SAGE) library subtraction and reverse transcription polymerase chain reaction to further examine interesting clusters. Four novel genes were identified and labeled: endothelial cell-specific molecules (ECSM) 1-3 and magic roundabout (similar to the axon guidance protein roundabout). In summary, we present a powerful novel approach for comparative expression analysis combining two datamining strategies followed by experimental verification.

Adult↗
PubMed2001

The N-terminal leucine-rich regions in Slit are sufficient to repel olfactory bulb axons and subventricular zone neurons.

The Slit proteins are a new family of secreted guidance cues involved in axon guidance and neuronal migration. Each mammalian Slit protein contains >1400 amino acid residues, with four leucine-rich regions (LRRs), nine epidermal growth factor repeats, a laminin G domain, and a C-terminal cysteine-rich domain. A receptor for Slit is the transmembrane protein Roundabout (Robo), whose extracellular part contains five Ig domains and three fibronectin type III repeats. We report here that the LRRs in Slit are sufficient for binding to the Ig domains of Robo. Mutant forms of Slit containing only the LRRs function as chemorepellents for axons projecting from the olfactory bulb both in vitro and in the telencephalon. The LRRs can repel neurons migrating from the anterior subventricular zone (SVZa) to the olfactory bulb in brain slices isolated from neonatal rodents. However, the LRRs do not show repulsive effects on the SVZa neurons migrating in collagen gels. Our results indicate that the same LRRs are sufficient for guiding both axon projection and neuronal migration and suggest that the other regions in the Slit proteins may be involved in regulating the diffusion and distribution of the Slit proteins. The fact that the same domains are involved in guiding axon projection and neuronal migration further strengthens the idea of a conserved guidance mechanism for these important processes.

Amino Acid Motifs↗
PubMed2002

Magic roundabout is a new member of the roundabout receptor family that is endothelial specific and expressed at sites of active angiogenesis.

We have used bioinformatic data mining to identify a novel, endothelial-specific gene encoding a protein with homology to the axon guidance protein roundabout (ROBO1). The new gene has been called magic roundabout (ROBO4; GenBank acc. no. AF361473) and is smaller than other members of the roundabout gene family. Thus, in the extracellular region, magic roundabout has only two of the five immunoglobulin and two of the three fibronectin domains present in other roundabout genes. Expression of magic roundabout in vitro was detected in only endothelial cells and was greater in cells exposed to hypoxia. In situ hybridization and immunohistochemistry validated the bioinformatic prediction that magic roundabout expression would be endothelial specific in vivo. Magic roundabout expression in the adult was restricted exclusively to sites of active angiogenesis, notably tumor vessels. The identification of magic roundabout shows that the roundabout gene family extends beyond neuronal tissue and that roundabout/slit interactions are likely to have a role in angiogenesis.

Amino Acid Sequence↗
PubMed1999

Cloning and functional studies of a novel gene aberrantly expressed in RB-deficient embryos.

The tumor suppressor RB regulates diverse cellular processes such as G1/S transition, cell differentiation, and cell survival. Indeed, Rb-knockout mice exhibit phenotypes including ectopic mitosis, defective differentiation, and extensive apoptosis in the neurons. Using differential display, a novel gene, Rig-1, was isolated based on its elevated expression in the hindbrain and spinal cord of Rb-knockout embryos. The longest open reading frame of Rig-1 encoded a polypeptide that consists of a putative extracellular segment with five immunoglobulin-like domains and three fibronectin III-like domains, a putative transmembrane domain, and a distinct intracellular segment. The Rig-1 sequence was 40% identical to the recently identified roundabout protein. Consistent with the predicted transmembrane nature of the protein, Rig-1 protein was present in the membranous fraction. Antisera raised against the putative extracellular and intracellular segments of Rig-1 reacted with an approximately 210-kDa protein in mouse embryonic CNS. Rig-1 mRNA was transiently expressed in the embryonic hindbrain and spinal cord. Elevated levels of Rig-1 mRNA and protein were found in Rb-/- embryos. Ectopic expression of a transmembrane form of Rig-1, but not the secreted form, promoted neuronal cell entrance to S phase and repressed the expression of a marker of differentiated neuron, Talpha1 tubulin. Thus Rig-1, a possible distant relative of roundabout, may mediate some of the pleiotropic roles of RB in the developing neurons.

Alternative Splicing↗
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

Alterations of the Dutt1/Robo1 gene in lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine in rats.

Abnormalities of tumor suppressor genes (TSGs) on chromosome 3p are known to be important for the development of human lung cancers. In the present study, we investigated alterations of the Dutt1/Robo1 gene, as a possible tumor suppressor in this region, in rat lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine (BHP). Male Wistar rats, 6-wk-old, were given 2000 ppm BHP in their drinking water for 12 wk and maintained without further treatment until killed at wk 25. A total of 12 lung adenocarcinomas were obtained and total RNAs were extracted from each for assessment of aberrant transcripts of the Dutt1/Robo1 gene by reverse transcription (RT)-polymerase chain reaction (PCR) analysis. Aberrant transcripts bearing deletions of nucleotides (nt) 55-4318, 89-4346, 605-4221, and 929-4318 were detected in four of 12 adenocarcinomas (33.3%). Loss or reduced expression of the Dutt1/Robo1 gene was not found in any of the adenocarcinomas. Genomic DNAs extracted from six adenocarcinomas for Southern blot analysis did not show any evidence of deletion or gross rearrangement of the Dutt1/Robo1 gene. These results suggest that alterations of the Dutt1/Robo1 gene may be involved in the development of some lung adenocarcinomas induced by BHP in rats.

Adenocarcinoma↗
PubMed1998

The DUTT1 gene, a novel NCAM family member is expressed in developing murine neural tissues and has an unusually broad pattern of expression.

A new member of the NCAM family mapping to 3p12 has been isolated and predicted to be arranged in five immunoglobulin-like domains and three fibronectin-like domains which are particularly homologous to L1. There is a transmembrane domain and a long cytoplasmic region with no detectable homology to other sequences. Although less closely related to DCC, another family member, both share a loop of positively charged amino acids within the first immunoglobulin domain, unique to these two members of this very large gene family. Preliminary studies of expression in mouse embryos support an inferred role in neural development, but the observation of widespread gene expression in adult human tissues indicates that this protein has additional functions to those performed in neural cells.

Amino Acid Sequence↗
PubMed2006

Alternatively spliced Robo2 isoforms in zebrafish and rat.

Robo2, a member of the robo gene family, functions as a repulsive axon guidance receptor as well as a regulator of cell migration and tissue morphogenesis in different taxa. In this study, a novel isoform of the zebrafish robo2 (robo2_tv2), which included an otherwise alternatively spliced exon (CAE), has been characterized. Robo2_tv2 is expressed differentially in most non-neuronal tissues of adult zebrafish whereas robo2_tv1 expression to a great extent is restricted to the brain and eye. In zebrafish, robo2_tv2 exhibits a very-low-level basal expression starting from 1 day post fertilization until the mid-larval stages, at which time its expression increases dramatically and could be detected throughout adulthood. Our findings demonstrate that the amino acid sequence coded by CAE of the robo2 gene is highly conserved between zebrafish and mammals, and also contains conserved motifs shared with robo1 and robo4 but not with robo3. Furthermore, we provide an account of differential transcription of the CAE homolog in various tissues of the adult rat. These results suggest that the alternatively spliced robo2 isoforms may exhibit tissue specificity.

Alternative Splicing↗
PubMed2004

Axon guidance: mice and men need Rig and Robo.

For many growing axons, navigating across the midline of the nervous system is a crucial stage of their development. New studies on mice and humans show that the axon guidance receptor Robo3/Rig1 is indispensable for axons to accomplish this task.

Animals↗
PubMed2005

Netrin-1 and slit-2 regulate and direct neurite growth of ventral midbrain dopaminergic neurons.

We investigated the roles of netrin-1 and slit-2 in regulation and navigation of dopamine (DA) axon growth using an explant culture preparation of embryonic ventral midbrain (embryonic day 14) and a co-culture system. We found that netrin-1 protein significantly enhanced DA axonal outgrowth and promoted DA axonal outgrowth in a co-culture system of netrin-1 expressing cells. Such effects were mediated by the receptor DCC as demonstrated by antibody perturbation of the DCC receptor. In contrast, slit-2 inhibited DA neuron extensions and repelled DA neurite growth. These slit-2 activities required robo receptors since the reduced neurite extension was abolished by addition of excess robo receptors. In this system, netrin-1 stimulated and slit-2 opposed DA neurite growth. Such regulation may be important for DA axonal maintenance, regeneration, and phenotypic target recognition.

Animals↗
PubMed2004

Dendritic guidance.

Like axons, dendrites need guidance for proper orientation and positioning within the brain. Guidance determines synaptic connectivity as well as the strength of transmission. Recent in vivo studies have demonstrated that several cell-surface receptors, previously known as axon guidance molecules, are also responsible for the directed outgrowth of dendrites. Collectively, these studies reveal that the function of guidance molecules in individual neurons and individual processes is diverse and likely to be specifically regulated. Here, these studies are reviewed and emerging issues and implications are discussed.

Animals↗
PubMed1998

The conserved immunoglobulin superfamily member SAX-3/Robo directs multiple aspects of axon guidance in C. elegans.

The C. elegans sax-3 gene encodes a predicted transmembrane protein with five immunoglobulin domains and three fibronectin type III repeats that is closely related to Drosophila Robo. Mutations in sax-3 lead to repeated midline crossing by ventral cord axons that normally do not cross the midline after they join the ventral cord, a phenotype similar to that of robo mutants. sax-3 is also required for guidance of some axons to the ventral cord, implicating this gene in two different types of guidance events. A sax-3::GFP fusion gene is expressed in developing neurons during axon outgrowth, and sax-3 function is required at the time of axon guidance, suggesting that this gene mediates cell interactions during guidance decisions.

Amino Acid Sequence↗
PubMed2002

Pathfinding and error correction by retinal axons: the role of astray/robo2.

To address how the highly stereotyped retinotectal pathway develops in zebrafish, we used fixed-tissue and time-lapse imaging to analyze morphology and behavior of wild-type and mutant retinal growth cones. Wild-type growth cones increase in complexity and pause at the midline. Intriguingly, they make occasional ipsilateral projections and other pathfinding errors, which are always eventually corrected. In the astray/robo2 mutant, growth cones are larger and more complex than wild-type. astray axons make midline errors not seen in wild-type, as well as errors both before and after the midline. astray errors are rarely corrected. The presumed Robo ligands Slit2 and Slit3 are expressed near the pathway in patterns consistent with their mediating pathfinding through Robo2. Thus, Robo2 does not control midline crossing of retinal axons, but rather shapes their pathway, by both preventing and correcting pathfinding errors.

Animals↗