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At least 19 recordsLinked to original sources
PubMed1999

Identification of semaphorin E gene expression in metastatic human lung adenocarcinoma cells by mRNA differential display.

UNLABELLED: Human lung adenocarcinoma cell lines HAL-8Luc and HAL-24Luc differ in their metastatic potential. HAL-8Luc cells metastasize to lungs when injected either intravenously or intramuscularly. in mice while HAL-24Luc cells do not. The differential display method is used to identify genes differentially expressed between the two cell lines and the findings are extensively discussed. BACKGROUND: Lung cancer is the leading form of cancer in most countries, and metastasis is the main cause of death in oncological patients. The metastatic phenotype of tumor cells is the result of genetic events altering the RNA and protein expression of normal cells. Our objective was to identify genes expressed differentially between metastatic and nonmetastatic human lung adenocarcinoma cells that might be used as a prognostic factor. METHODS: The differential display technique was used to compare the RNA expression patterns distinguishing metastatic (HAL-8Luc) and nonmetastatic (HAL-24Luc) human lung adenocarcinoma cells, two genetically close cell lines. RESULTS: Differential expression of three cDNAs was confirmed by Northern blot analysis. Two sequences corresponding to a putative splicing factor and a proliferation-related factor cDNAs were underexpressed in the metastatic cells relative to the nonmetastatic ones. Interestingly, we found that human semaphorin E mRNA was several fold overexpressed in the metastatic cells. This recently identified gene encodes a protein whose expression has been related to several cell survival mechanisms as well as to immunosuppression. CONCLUSION: Our results point to the relevance of semaphorin E in metastatic spread of human lung adenocarcinoma cells.

Adenocarcinoma↗
PubMed1996

Anatomy of rat semaphorin III/collapsin-1 mRNA expression and relationship to developing nerve tracts during neuroembryogenesis.

Semaphorin III/collapsin-1 (semaIII/coll-1) is a chemorepellent that exhibits a repulsive effect on growth cones of dorsal root ganglion neurons. To identify structures that express semaIII/coll-1 in developing mammals, we cloned the rat homologue and performed in situ hybridization on embryonic, neonatal, and adult rats. The relationship between semaIII/coll-1 mRNA distribution and developing nerve tracts was studied by combining in situ hybridization with immunohistochemistry for markers of growing nerve fibers. At embryonic day 11, semaIII/coll-1 expression was restricted to the olfactory pit, the basal and rostral surface of the telencephalic vesicle, the anlage of the eye, the epithelium of Rathke's pouch, and the somites. At later developmental stages, semaIII/coll-1 mRNA was found to be widely distributed in neuronal as well as in mesenchymal and epithelial structures outside the nervous system. Strong expression was found in the olfactory bulb, retina, lens, piriform cortex, amygdalostriatal area, pons, cerebellar anlage, motor nuclei of cranial nerves, and ventral spinal cord. After birth, mesenchymal staining decreased rapidly and expression became progressively restricted to specific sets of neurons in the central nervous system (CNS). In the mature CNS, semaIII/coll-1 mRNA remains detectable in mitral cells, neurons of the accessory bulb and cerebral cortex, cerebellar Purkinje cells, as well as a subset of cranial and spinal motoneurons. The temporal and spatial expression pattern of semaIII/coll-1 mRNA and its relationship to emerging nerve tracts suggests that semaIII/coll-1 is involved in guiding growing axons towards their targets by forming a molecular boundary that instructs axons to engage in the formation of specific nerve tracts.

Animals↗
PubMed1998

Anatomical distribution of the chemorepellent semaphorin III/collapsin-1 in the adult rat and human brain: predominant expression in structures of the olfactory-hippocampal pathway and the motor system.

Alterations in neuronal connectivity of the mature central nervous system (CNS) appear to depend on a delicate balance between growth-promoting and growth-inhibiting molecules. To begin to address a potential role of the secreted chemorepulsive protein semaphorin(D)III/collapsin-1 (semaIII/coll-1) in structural plasticity during adulthood, we used high-resolution nonradioactive in situ hybridization to identify neural structures that express semaIII/coll-1 mRNA in the mature rat and human brain. SemaIII/coll-1 was expressed in distinct but anatomically and functionally linked structures of the adult nervous system. The olfactory-hippocampal pathway displayed semaIII/coll-1 expression in a continuum of neuronal structures, including mitral and tufted cells of the olfactory bulb, olfactory tubercle, and piriform cortex; and distinct nuclei of the amygdaloid complex, the superficial layers of the entorhinal cortex, and the subiculum of the hippocampal formation. In addition, prominent labeling was found in neuronal components of the motor system, particularly in cerebellar Purkinje cells and in subpopulations of cranial and spinal motoneurons. Retrograde tracing combined with in situ hybridization also revealed that the staining of semaIII/coll-1 within the entorhinal cortex was present in the stellate neurons that project via the perforant path to the molecular layer of the dentate gyrus. Like in the rat, the human brain displayed discrete expression of semaIII/coll-1. Among the structures examined, the most prominent staining was observed in the cellular islands of the superficial layers of the human entorhinal cortex. The constitutive expression of the chemorepellent semaIII/coll-1 in discrete populations of neurons in the mature rat and human CNS raises the possibility that, in addition to its function as repulsive axon guidance cue during development, semaIII/coll-1 might be involved in restricting structural changes that occur in the wiring of the intact CNS.

Adult↗
PubMed1997

A novel action of collapsin: collapsin-1 increases antero- and retrograde axoplasmic transport independently of growth cone collapse.

Chick collapsin-1, a member of the semaphorin family, has been implicated in axonal pathfinding as a repulsive guidance cue. Collapsin-1 induces growth cone collapse via a pathway which may include CRMP-62 and heterotrimeric G proteins. CRMP-62 protein is related to UNC-33, a nematode neuronal protein required for appropriately directed axonal extension. Mutations in unc-33 affect neural microtubules, the basic cytoskeletal elements for axoplasmic transport. Using computer-assisted video-enhanced differential interference contrast microscopy, we now demonstrate that collapsin-1 potently promotes axoplasmic transport. Collapsin-1 doubles the number of antero- and retrograde-transported organelles but not their velocity. Collapsin-1 decreases the number of stationary organelles, suggesting that the fraction of time during which a particle is moving is increased. Collapsin-1-stimulated transport occurs by a mechanism distinct from that causing growth cone collapse. Pertussis toxin (PTX) but not its B oligomer blocks collapsin-induced growth cone collapse. The holotoxin does not affect collapsin-stimulated axoplasmic transport. Mastoparan and a myelin protein NI-35 induce PTX-sensitive growth cone collapse but do not stimulate axoplasmic transport. These results provide evidence that collapsin has a unique property to activate axonal vesicular transport systems. There are at least two distinct pathways through which collapsin exerts its actions in developing neurons.

Animals↗
PubMed1997

Retinal axon growth cone responses to different environmental cues are mediated by different second-messenger systems.

Numerous studies have shown that the developing tip of a neurite, the growth cone, can respond to environmental cues with behaviors such as guidance or collapse. To assess whether a given cell type can use more than one second-messenger pathway for a single behavior, we compared the influence of two well-characterized guidance cues on growth cones of chick temporal retinal ganglion cells. The first cue was the repulsive activity derived from the posterior optic tectum (p-membranes), and the second was the collapse-inducing activity derived from oligodendrocytes known as NI35/NI250. p-Membranes caused permanent growth cone collapse with no recovery after several hours, while NI35 caused transient collapse followed by recovery after about 10 min. The p-membrane-induced collapse was found to be Ca2+ independent, as shown using the Ca2+-sensitive dye Fura-2 and by the persistence of collapse in Ca2+-free medium. Dantrolene, a blocker of the ryanodine receptor, had only a minor effect on the collapse frequency caused by p-membranes. In contrast, the NI35-induced collapse was clearly Ca2+ dependent. [Ca2+]i increased sevenfold preceding collapse, and both dantrolene and antibodies against NI35 significantly reduced both the Ca2+ increase and the collapse frequency. Thus, even in a single cell type, growth cone collapse induced by two different signals can be mediated by two different second-messenger systems.

Animals↗
PubMed1999

Growth cone neuropilin-1 mediates collapsin-1/Sema III facilitation of antero- and retrograde axoplasmic transport.

Collapsin-1/Sema III, a member of the semaphorin family, has been implicated in axonal pathfinding as a repulsive guidance cue. Cellular and molecular mechanisms by which collapsin-1 exerts its action are not fully understood. Collapsin-1 induces growth cone collapse via a pathway which may include neuropilin-1, a cellsurface collapsin-1 binding protein, as well as intracellular CRMP-62 and heterotrimeric G proteins. We previously identified a second action of collapsin-1, the facilitation of antero- and retrograde axoplasmic transport. This response occurs via a mechanism distinct from that causing growth cone collapse. To investigate the possible involvement of neuropilin-1 in the action of collapsin-1 on axoplasmic transport, we produced a soluble neuropilin-1 (sNP-1) lacking the transmembrane and intracellular region. sNP-1 progressively displaced the dose-response curve for collapsin-1 to induce growth cone collapse to higher concentrations. sNP-1 also inhibited collapsin-1-induced augmentation of both antero- and retrograde axoplasmic transport. Furthermore, an anti-neuropilin-1 antibody blocked the collapsin-induced axoplasmic transport. These results together indicate that neuropilin-1 mediates collapsin-1 action on axoplasmic transport. To visualize collapsin-1 binding to endogenous neuropilin-1, we used a truncated collapsin-1-alkaline phosphatase fusion protein (CAP-4). CAP-4 stains the growth cone, neurite, and cell body. However, local application of collapsin-1 to growth cone but to neither neurite nor cell body promotes axoplasmic transport. Thus, growth cone NP-1 mediates the facilitatory action of collapsin-1 on antero- and retrograde axoplasmic transport.

Alkaline Phosphatase↗
PubMed1995

The guidance molecule semaphorin III is expressed in regions of spinal cord and periphery avoided by growing sensory axons.

The protein collapsin was purified from chick brain on the basis of its ability to inhibit sensory neuron growth cones, implicating this molecule in sensory axon guidance (Luo et al. [1993] Cell 75:217-227). To examine the relationship between collapsin and sensory axon growth, we examined the pattern of mRNA expression of collapsin's mammalian paralogue, Semaphorin III (Sema III), and compared it to dorsal root ganglion (DRG) axon pathways in the developing rat embryo. Centrally, DRG axons enter the spinal cord by embryonic (E) 11 and branch into the gray matter by E15 in brachial and thoracic regions. Laminar specific targets are reached by E17. Between E13 and E17, Sema III mRNA is expressed at high levels in the entire ventral half of the spinal cord except the floor plate. This pattern suggests that Sema III may inhibit non-proprioceptive sensory axons from penetrating the ventral spinal cord. Peripherally, sensory axons have entered the anterior sclerotome by E11 at all rostrocaudal levels. At this age, Sema III mRNA is already expressed in the dermamyotome and ventral aspect of the posterior sclerotome, areas which axons pass between but do not penetrate en route to their peripheral targets. From E12 to E15, the axons lengthen and branch into smaller fascicles which extend toward peripheral targets. During this time, Sema III mRNA is expressed by many mesodermal structures surrounding the axon fascicles, with highest levels observed in the dermamyotome, perinotochordal mesenchyme, pelvic girdle, and limb. As development proceeds, Sema III mRNA expression is quickly downregulated before disappearing by birth. Taken together, our results demonstrate that the gene for Sema III is expressed in central and peripheral regions which are avoided by growing DRG axons. These findings are consistent with the idea that Sema III inhibits growth and branching of axons into inappropriate areas during development.

Animals↗
PubMed1996

The distribution of collapsin-1 mRNA in the developing chick nervous system.

Collapsin-1 is a secreted glycoprotein that inhibits the extension of specific growth cones in vitro. It has been hypothesized to serve as a repulsive guidance cue for extending growth cones in vivo. Here we report the distribution of collapsin-1 message as demonstrated by in situ hybridization using digoxigenin-labeled RNA probes in wholemounts and tissue sections. In the early chick brain collapsin-1 is expressed in specific regions of the retina, the olfactory bulb, and the diencephalon. In the hindbrain collapsin-1 is first expressed in rhombomere 5 and later in bilaterally symmetric rostrocaudal stripes. Collapsin-1 is expressed in high levels in the ventral horn of the spinal cord and in ventricular stripes that extend rostrally to the hindbrain. In the periphery, collapsin-1 is expressed in the dermamyotome and in ectoderm and epidermis. Based on collapsin's expression patterns we tested axons extending from explants of ventral spinal cord and olfactory bulb for sensitivity to collapsin and show that the former are sensitive to collapsin whereas the latter are not. The distribution of collapsin mRNA is consistent with it playing a role in the organization of sensory axonal projections within the spinal cord and skin.

Animals↗
PubMed1999

Collapsin-1/semaphorin D is a repellent for chick ganglion of Remak axons.

Chick collapsin-1/human semaphorin III/mouse semaphorin D is believed to guide the extension of specific axons by a repellent mechanism. Here we examine its role in the guidance of axons of the ganglion of Remak (Remak) in the developing chick intestine. Early in embryogenesis Remak axons extend parallel to, but do not enter, the intestine when collapsin-1 is expressed in the adjacent rectal wall. Remak axons later penetrate the peripheral portions of the rectal wall when collapsin-1 expression retreats from the outer muscle layer to the more internal submucosal and mucosal layers of the rectum. Extension of Remak neurites is repelled in vitro by rectum explants and also by 293T cells expressing collapsin-1. The rectal chemorepellent activity is blocked by anti-collapsin-1 antibodies. Our results suggest that collapsin-1 may help prevent Remak axons from projecting into the intestinal wall at early developmental times and later restricts Remak axon trajectories to the outer part of the intestinal muscle layer.

Alkaline Phosphatase↗
PubMed1999

Embryonic lens repels retinal ganglion cell axons.

During development of the vertebrate visual system, retinal ganglion cell (RGC) axons follow a precise path toward their midbrain targets. Although much is known about the cues that direct RGC axons once they have left the optic disc, less is known about the guidance of axons at earlier stages, when RGCs first send out their axons to navigate within the developing retina. Using collagen gel coculture experiments, we find that the embryonic lens produces a powerful diffusible repulsive activity for RGC axons. We also find that this activity is localized to the lens epithelium and not the lens fiber layer, while the pigmented epithelium and vitreous humour are devoid of activity. The further observation that the lens also chemorepels primary sensory axons, but does not repel olfactory bulb axons, shows that this activity is specific for subsets of axons. Our experiments have excluded two candidate repellents for RGC axons (collapsin-1/sema III and chondroitin sulfate proteoglycans). These results implicate the lens in the earliest stages of RGC axon guidance. One function of the lens repellent may be to prevent aberrant targeting toward the lens, and it may also be involved in the directional guidance of RGC axons toward the optic disc.

Animals↗
PubMed1998

Regulation of semaphorin III/collapsin-1 gene expression during peripheral nerve regeneration.

The competence of neurons to regenerate depends on their ability to initiate a program of gene expression supporting growth and on the growth-permissive properties of glial cells in the distal stump of the injured nerve. Most studies on intrinsic molecular mechanisms governing peripheral nerve regeneration have focussed on the lesion-induced expression of proteins promoting growth cone motility, neurite extension, and adhesion. However, little is known about the expression of intrinsic chemorepulsive proteins and their receptors, after peripheral nerve injury and during nerve regeneration. Here we report the effect of peripheral nerve injury on the expression of the genes encoding sema III/coll-1 and its receptor neuropilin-1, which are known to be expressed in adult sensory and/or motor neurons. We have shown that peripheral nerve crush or transection results in a decline in sema III/coll-1 mRNA expression in injured spinal and facial motor neurons. This decline was paralleled by an induction in the expression of the growth-associated protein B-50/GAP-43. As sema III/coll-1 returned to normal levels following nerve crush, B-50/GAP-43 returned to precrush levels. Thus, the decline in sema III/coll-1 mRNA coincided with sensory and motor neuron regeneration. A sustained decline in sema III/coll-1 mRNA expression was found when regeneration was blocked by nerve transection and ligation. No changes were observed in neuropilin-1 mRNA levels after injury to sensory and motor neurons, suggesting that regenerating peripheral neurons continue to be sensitive to sema III/coll-1. Therefore we propose that a decreased expression of sema III/coll-1, one of the major ligands for neuropilin-1, during peripheral nerve regeneration is an important molecular event that is part of the adaptive response related to the success of regenerative neurite outgrowth occurring following peripheral nerve injury.

Animals↗
PubMed1996

Isolation of the human semaphorin III/F gene (SEMA3F) at chromosome 3p21, a region deleted in lung cancer.

Small cell lung cancer (SCLC) has been correlated with a deletion in the short arm of chromosome 3, with the region 3p21 being lost from one homolog in almost all cases. Two SCLC cell lines have homozygous deletions in 3p21, and these deletions overlap with a fragment of chromosome 3 that has tumor suppression activity in vivo. We have isolated some cDNA clones from this region that are homologous to the genes constituting the semaphorin family. They represent a novel human semaphorin, termed sema III/F (HGMW-approved symbol SEMA3F), which is expressed as a 3.8-kb transcript in a variety of cell lines and tissues; it is detected as early as Embryonic Day 10 in mouse development. There is high expression in mammary gland, kidney, fetal brain, and lung and lower expression in heart and liver. Although there is reduced expression of this gene in several SCLC lines, no mutations were found. This semaphorin homolog has characteristics of a secreted member of the semaphorin III family, with 52% identity with mouse semaphorin E and 49% identity with chicken collapsin/semaphorin D.

Amino Acid Sequence↗
PubMed1996

The sensory innervation of the mouse spinal cord may be patterned by differential expression of and differential responsiveness to semaphorins.

To better understand the regulatory processes underlying axonal pathfinding we analyzed the embryonic expression of seven murine semaphorin genes by in situ hybridization In the spinal cord, transcripts of all seven semaphorin genes were detected from Embryonic Day 11.5 (E11.5) onward and restricted to distinct regions at E15.5. Interestingly, semE, F, and G mRNAs were in addition differentially expressed in the ventricular zone of the telencephalon. In order to correlate these expression patterns to the behavior of different types of sensory afferents, we tested their response to recombinant semaphorin proteins. Specific subpopulations of dorsal root ganglion sensory neurons displayed a developmentally regulated differential response to Sem D. Whereas extension of both NGF- and NT-3-dependent neurites was inhibited by Sem D at E12.5, only neurites formed in the presence of NGF responded at E14.5. This suggests that Sem D may be involved in preventing an early penetration of the spinal cord by sensory afferents and subsequently shaping their lamina-specific termination.

Animals↗
PubMed1997

Structural features of collapsin required for biological activity and distribution of binding sites in the developing chick.

We have used Fc-chimeras of collapsin-1/Sema III to study the structure-function activity of this recently identified repulsive axonal guidance molecule and to map the distribution of its binding sites during chick development. Our results show that the biological activity of the collapsin-Fc in an in vitro collapse assay is independent of both the Ig-domain and the positive charged carboxy terminus. Collapsin binding sites were found on a number of neuronal fiber tracts, and in two instances (DRG tracts and the retinotectal projection) this expression is both highly dynamic and consistent with them playing a role in axonal growth and guidance. Collapsin-1 binding sites were also found on a number of nonneuronal structures that do not produce collapsin-1 mRNA. We postulate that these sites may act to localize or concentrate collapsin-1 released from growing axons and in this way allow for an autocrine axonal guidance mechanism to function during development.

Animals↗
PubMed1998

Neurotrophins rapidly modulate growth cone response to the axon guidance molecule, collapsin-1.

We show that neurotrophins acting at the growth cone via Trk receptors can mediate rapid and distinct changes in growth cone response to collapsin-1, an inhibitory axon guidance molecule. We find that the sensitivity of growth cones of dorsal root ganglia (DRG) neurons to collapsin-1 differs when chronically cultured in BDNF, NT-3, or NGF with those in BDNF most sensitive and those in NGF least sensitive. Further, growth cones chronically cultured in BDNF rapidly decrease their sensitivity to collapsin-1 with acute exposure to NGF. Conversely, growth cones chronically cultured in NGF rapidly increase their sensitivity to collapsin-1 with acute exposure to BDNF. These bidirectional effects of neurotrophins appear to be mediated by the neurotrophin-specific Trk receptors on the growth cones since most growth cones are immunopositive for TrkA and TrkB, the NGF and BDNF receptors, respectively, and k252a, a selective inhibitor of Trk-mediated responses to neurotrophins, diminishes collapsin-1-induced growth cone collapse. These findings indicate that the response of growth cones to axon guidance molecules is dynamic and can be rapidly and differentially modulated by neurotrophins.

Animals↗
PubMed1998

Many major CNS axon projections develop normally in the absence of semaphorin III.

The semaphorins constitute a large gene family of transmembrane and secreted molecules, many of which are expressed in the nervous system. Genetic studies in Drosophila have revealed a role for semaphorins in axon guidance and synapse formation, and several in vitro studies in mice have demonstrated a dramatic chemorepellent effect of semaphorin III (Sema III) on the axons of several populations of neurons. To investigate the function of Sema III during in vivo axon guidance in the mammalian CNS, we studied the development of axonal projections in mutant mice lacking Sema III. Projections were studied for which either the in vitro evidence suggests a role for Sema III in axon guidance (e.g., cerebellar mossy fibers, thalamocortical axons, or cranial motor neurons) or the in vivo expression suggests a role for Sema III in axon guidance (e.g., cerebellar Purkinje cells, neocortex). We find that many major axonal projections, including climbing fiber, mossy fiber, thalamocortical, and basal forebrain projections and cranial nerves, develop normally in the absence of Sema III. Despite its in vitro function and in vivo expression, it appears as if Sema III is not absolutely required for the formation of many major CNS tracts. Such data are consistent with recent models suggesting that axon guidance is controlled by a balance of forces resulting from multiple guidance cues. Our data lead us to suggest that if Sema III functions in part to guide the formation of major axonal projections, then it does so in combination with both other semaphorins and other families of guidance molecules.

Animals↗
PubMed1999

Expression of the gene encoding the chemorepellent semaphorin III is induced in the fibroblast component of neural scar tissue formed following injuries of adult but not neonatal CNS.

This study evaluates the expression of the chemorepellent semaphorin III (D)/collapsin-1 (sema III) following lesions to the rat CNS. Scar tissue, formed after penetrating injuries to the lateral olfactory tract (LOT), cortex, perforant pathway, and spinal cord, contained numerous spindle-shaped cells expressing high levels of sema III mRNA. The properties of these cells were investigated in detail in the lesioned LOT. Most sema III mRNA-positive cells were located in the core of the scar and expressed proteins characteristic for fibroblast-like cells. Neuropilin-1, a sema III receptor, was expressed in injured neurons with projections to the lesion site, in a subpopulation of scar-associated cells and in blood vessels around the scar. In contrast to lesions made in the mature CNS, LOT transection in neonates did not induce sema III mRNA expression within cells in the lesion and was followed by vigorous axonal regeneration. The concomitant expression of sema III and its receptor neuropilin-1 in the scar suggests that sema III/neuropilin-1-mediated mechanisms are involved in CNS scar formation. The expression of the secreted chemorepellent sema III following CNS injury provides the first evidence that chemorepulsive semaphorins may contribute to the inhibitory effects exerted by scars on the outgrowth of injured CNS neurites. The vigorous regrowth of injured axons in the absence of sema III following early neonatal lesions is consistent with this notion. The inactivation of sema III in scar tissue by either antibody perturbation or by genetic or pharmacological intervention could be a powerful means to promote long-distance regeneration in the adult CNS.

Animals↗
PubMed1999

Role of semaphorin III in the developing rodent trigeminal system.

Semaphorins are a large family of secreted and transmembrane glycoproteins. Sema III, a member of the Class III semaphorins is a potent chemorepulsive signal for subsets of sensory axons and steers them away from tissue regions with high levels of expression. Previous studies in mutant mice lacking sema III gene showed various neural and nonneural abnormalities. In this study, we focused on the developing trigeminal pathway of sema III knockout mice. We show that the peripheral and central trigeminal projections are impaired during initial pathway formation when they develop into distinct nerves or tracts. These axons defasciculate and compromise the normal bundling of nerves and restricted alignment of the central tract. In contrast to trigeminal projections, thalamocortical projections to the barrel cortex appear normal. Furthermore, sema III receptor, neuropilin, is expressed during a short period of development when the tract is laid down, but not in the developing thalamocortical pathway. Peripherally, trigeminal axons express neuropilin for longer duration than their central counterparts. In spite of projection errors, whisker follicle innervation appears normal and whisker-related patterns form in the trigeminal nuclei and upstream thalamic and cortical centers. Our observations suggest that sema III plays a limited role during restriction of developing trigeminal axons to proper pathways and tracts. Other molecular and cellular mechanisms must act in concert with semaphorins in ensuring target recognition, topographic order of projections, and patterning of neural connections.

Animals↗