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At least 19 recordsLinked to original sources
PubMed1997

A 70 amino acid region within the semaphorin domain activates specific cellular response of semaphorin family members.

The semaphorin family contains secreted and transmembrane signaling proteins that function in the nervous, immune, and cardiovascular systems. Chick collapsin-1 is a repellent for specific growth cones. Two other secreted members of the semaphorin family, collapsin-2 and -3, are structurally similar to collapsin-1 but have different biological activities. Semaphorins contain a 500 amino acid family signature semaphorin domain. We show in this study that (1) the semaphorin domain of collapsin-1 is both necessary and sufficient for biological activity, (2) the semaphorin domain contains a 70 amino acid region that specifies the biological activity of the three family members, and (3) the positively charged carboxy terminus potentiates activity without affecting specificity. We propose that semaphorins interact with their receptors through two independent binding sites: one that mediates the biological response and one that potentiates it.

Amino Acid Sequence↗
PubMed1998

Human semaphorin K1 is glycosylphosphatidylinositol-linked and defines a new subfamily of viral-related semaphorins.

The semaphorin family contains a large number of secreted and transmembrane proteins, some of which are known to act as repulsive axon guidance cues during development or to be involved in immune function. We report here on the identification of semaphorin K1 (sema K1), the first semaphorin known to be associated with cell surfaces via a glycosylphosphatidylinositol linkage. Sema K1 is highly homologous to a viral semaphorin and can interact with specific immune cells, suggesting that like its viral counterpart, sema K1 could play an important role in regulating immune function. Sema K1 does not bind to neuropilin-1 or neuropilin-2, the two receptors implicated in mediating the repulsive action of several secreted semaphorins, and thus it likely acts through a novel receptor. In contrast to most previously described semaphorins, sema K1 is only weakly expressed during development but is present at high levels in postnatal and adult tissues, particularly brain and spinal cord.

Amino Acid Sequence↗
PubMed1998

New eukaryotic semaphorins with close homology to semaphorins of DNA viruses.

Semaphorins were initially described as a family of repulsive guidance molecules in embryonal development. Their basic structure consists of an N-terminal signal sequence, the defining semaphorin domain ofapproximately 500 amino acids, an Ig-like domain,and a variable carboxy-terminus. We recently described a viral semaphorin homologue encoded by the alcelaphine herpesvirus type 1. Less conserved, truncated homologues were also identified in poxviruses. Here we describe new human and murine semaphorin homologues. The respective genes were cloned and sequenced, and they were termed H-Sema-L and M-Sema-L (HGMW-approved symbols SEMAL and Semal, respectively). A multiply spliced mRNA of 3.2 kb is expressed in human placenta, spleen, thymus, and gonadal tissue. H-Sema-L maps to chromosome 15q22.3-q23 and M-Sema-L to the homologous locus 9A3.3-B in the mouse genome. The expression patterns and the presence of related genes in large DNA viruses suggest that this new semaphorin has a relevant function in the immune system.

Adjuvants, Immunologic↗
PubMed1997

Cloning and expression of a novel murine semaphorin with structural similarity to insect semaphorin I.

We describe a novel semaphorin family member, Sema VIa, with 25-36% sequence identity at the amino acid level in the semaphorin domain to previously published mouse homologues. This novel family member shares considerable homology with the best characterized murine semaphorin, Sema III (also known as SemD), at the 5' end but is divergent from Sema III near the 3' end because it contains a putative transmembrane domain. Remarkably, of the known semaphorins, Sema VIa bears the greatest structural similarity to insect Sema I, although it contains a much larger intracellular domain. We propose, therefore, that Sema VIa is the prototype of a new class (class VI) of semaphorins. In order to gain insights into potential functions of Sema VIa, we have compared mRNA expression of Sema VIa to that of Sema III during development. In the nervous system, Sema VIa is expressed in strikingly localized and transient patterns that are markedly different from those of Sema III. Interestingly, Sema VIa and Sema III frequently exhibit complementary or adjacent loci of expression. We suggest that Sema VIa may be important to nervous system development via a mechanism that involves cell-cell communication.

Amino Acid Sequence↗
PubMed1999

Cloning and characterization of a novel class VI semaphorin, semaphorin Y.

Semaphorins comprise a large family of proteins implicated in axonal guidance. We cloned a novel transmembrane semaphorin, semaphorin Y (Sema Y), which has a class VI sema domain. Sema Y shows growth cone collapsing activity on DRG neurons in vitro, and the target regions of the DRG neurons express sema Y mRNA during development. Sema Y may be a stop signal for these neurons in their target areas. Interestingly, sema Y mRNA was also detected in other neurons and their targets. Two isoforms of Sema Y derived from alternative splicing were identified and their expression was found to be regulated in a tissue- and age-dependent manner. Distribution of sema Y mRNA suggests that Sema Y might also be important during maintenance of axonal connections and/or differentiation and migration of cells. Sequence comparison among class VI semaphorins revealed two short conserved sequence stretches in their cytoplasmic domains, suggesting interaction of these semaphorins with a common intracellular component(s).

Alternative Splicing↗
PubMed2001

Diverse gene expression and function of semaphorins in developing lung: positive and negative regulatory roles of semaphorins in lung branching morphogenesis.

BACKGROUND: Previously, we reported that Sema3A, one of the secreted repulsive axon guidance molecules, CRMP (collapsin response mediator protein)-2, a putative intracellular signalling molecule for Sema3A and Sema3A receptor neuropilin-1 are expressed in the developing lung. Sema3A inhibits branching morphogenesis of embryonic lung in organ culture. RESULTS: We examined the gene expression of Sema3A, Sema3C, Sema3F and their receptors, NP-1, NP-2 and plexin-A1 by in situ hybridization. Transcripts of all six genes were detected in mouse lung from embryonic day E11.5 to E17.5, and displayed highly specific spatiotemporal distributions. The distribution of the receptor genes was detected in patterns which were consistent with known receptor usage of the semaphorins. In contrast to Sema3A, we found that the other class 3 semaphorins, Sema3C and Sema3F, stimulated branching morphogenesis. This stimulatory effect of Sema3C or Sema3F was accompanied by a moderate increase in the incorporation of bromodeoxyuridine (BrdU) into DNA in the terminal epithelial cells. CONCLUSION: The coordinated expression patterns of different semaphorins and their receptors, together with the specific activities affecting branching morphogenesis, suggest that the semaphorins act as both positive and negative regulators of branching morphogenesis in the developing lung.

Animals↗
PubMed1998

A poxvirus-encoded semaphorin induces cytokine production from monocytes and binds to a novel cellular semaphorin receptor, VESPR.

The vaccinia virus A39R protein is a member of the semaphorin family. A39R.Fc protein was used to affinity purify an A39R receptor from a human B cell line. Tandem mass spectrometry of receptor peptides yielded partial amino acid sequences that allowed the identification of corresponding cDNA clones. Sequence analysis of this receptor indicated that it is a novel member of the plexin family and identified a semaphorin-like domain within this family, thus suggesting an evolutionary relationship between receptor and ligand. A39R up-regulated ICAM-1 on, and induced cytokine production from, human monocytes. These data, then, describe a receptor for an immunologically active semaphorin and suggest that it may serve as a prototype for other plexin-semaphorin binding pairs.

Amino Acid Sequence↗
PubMed2001

Human semaphorin 6B [(HSA)SEMA6B], a novel human class 6 semaphorin gene: alternative splicing and all-trans-retinoic acid-dependent downregulation in glioblastoma cell lines.

We have identified a novel human gene related to the class 6 semaphorin family of axon guidance molecules, termed human semaphorin 6B or (HSA)SEMA6B. Two splicing variants of this gene were identified by RT-PCR: (HSA)SEMA6B.1 (short isoform) and (HSA)SEMA6B.2 (longer isoform). Computational analysis suggests that these isoforms correspond to putative secreted and transmembranous semaphorins, respectively. The levels of (HSA)SEMA6B expression were evaluated by Northern blot analysis in different tissues and in some pathological and pharmacological conditions. We observed that (HSA)SEMA6B is highly expressed in human brain and at lower levels in a variety of other tissues. Interestingly, the (HSA)SEMA6B transcript was downregulated in two different human glioblastoma cell lines (T98G and A172) upon prolonged treatment with all-trans-retinoic acid, an anti-tumor and differentiation-inducing agent.

Alternative Splicing↗
PubMed2002

Semaphorin 1a and semaphorin 1b are required for correct epidermal cell positioning and adhesion during morphogenesis in C. elegans.

The semaphorin family comprises secreted and transmembrane proteins involved in axon guidance and cell migration. We have isolated and characterized deletion mutants of C. elegans semaphorin 1a (Ce-sema-1a or smp-1) and semaphorin 1b (Ce-sema-1b or smp-2) genes. Both mutants exhibit defects in epidermal functions. For example, the R1.a-derived ray precursor cells frequently fail to change anterior/posterior positions completely relative to their sister tail lateral epidermal precursor cell R1.p, causing ray 1 to be formed anterior to its normal position next to ray 2. The ray cells, which normally separate from the lateral tail seam cell (SET) at the end of L4 stage, remains connected to the SET cell even in adult mutant males. The ray 1 defects are partially penetrant in each single Ce-sema-1 mutant at 20 degrees C, but are greatly enhanced in Ce-sema-1 double mutants, suggesting that Ce-Sema-1a and Ce-Sema-1b function in parallel to regulate ray 1 position. Both mutants also have defects in other aspects of epidermal functions, including head and tail epidermal morphogenesis and touch cell axon migration, whereas, smp-1 mutants alone have defects in defecation and brood size. A feature of smp-1 mutants that is shared with mutants of mab-20 (which encodes Sema-2a) is the abnormal perdurance of contacts between epidermal cells.

Amino Acid Sequence↗
PubMed1997

Molecular cloning of a novel member of semaphorin family genes, semaphorin Z.

Semaphorins/collapsins (semaphorins) comprise a large family of proteins implicated in axonal guidance during development. We cloned a novel member (semaZ) of the semaphorin gene family from a rat brain cDNA library. Sema Z was thought to be an integral membrane glycoprotein of 887 amino acids including a sema domain composed of 532 amino acids. The amino acid sequence of Sema Z showed 28-35% identity with other semaphorins in its sema domain, including 15 conserved cysteine residues. The cytoplasmic domain of Sema Z was found to be rich in prolines. Our phylogenetic analysis based on the amino acid sequence of the sema domains and the location of conserved N-glycosylation sites suggested that the sema domain of Sema Z belongs to a new class, class VI. We detected the semaZ mRNA in the first branchial arch of embryonic day 11 (E11) rat embryo, and subsequently in the myotomes and the dorsal root ganglia in developing somites from E11.5 through E13.5, but not in the brain. However, at E15, 18, 21 and P0, semaZ was highly expressed in the brain. Sema Z might play a role in both peripheral and central nervous system development.

Amino Acid Sequence↗
PubMed2001

Semaphorin 4C, a transmembrane semaphorin, [corrected] associates with a neurite-outgrowth-related protein, SFAP75.

Semaphorin 4C (S4C, previously called M-SemaF) was recently identified as a brain rich transmembrane member of semaphorin family of the vertebrate. In the cytoplasmic domain of S4C there is a proline-rich region suggesting that the cytoplasmic domain may play an important role in Sema4C function. In this study, we have identified the cytoplasmic domain (cd) of M-SemaF(S4C)-associating protein with a Mr of 75 kDa, named SFAP75, from mouse brain. SFAP75 turned out to be the same as the recently reported neurite-outgrowth-related protein named Norbin. Deletion mutants analyses of S4C and SFAP75 revealed that the membrane-proximal region of S4Ccd binds to the intermediate region of SFAP75. Western blot and immunohistochemical analyses with anti-Sema4C and anti-SFAP75 antibodies indicated that S4C and SFAP75 were specially enriched in the brain with a similar distribution pattern to each other. These results suggest that S4C interacts with SFAP75 and plays a role in neural function in brain.

Animals↗
PubMed1998

Semaphorin-neuropilin interactions underlying sympathetic axon responses to class III semaphorins.

Neuropilin-1 and neuropilin-2 show specificity in binding to different class III semaphorins, including Sema III, Sema E, and Sema IV, suggesting that the specificity of action of these semaphorins is dictated by the complement of neuropilins expressed by responsive neurons. In support of this, we show that sympathetic axons coexpress neuropilin-1 and -2, that their responses to Sema III, Sema E, and Sema IV are affected in predicted ways by antibodies to neuropilin-1, and that neuropilin-1 and -2 can form homo- and heterooligomers through an interaction involving at least partly the neuropilin MAM (meprin, A5, mu) domain. These results support the idea that in sympathetic axons, the Sema III signal is mediated predominantly by neuropilin-1 oligomers, the Sema IV signal by neuropilin-2 oligomers, and the Sema E signal by neuropilin-1 and -2, either as homo- or heterooligomers.

Animals↗
PubMed2001

Age-dependent effects of secreted Semaphorins 3A, 3F, and 3E on developing hippocampal axons: in vitro effects and phenotype of Semaphorin 3A (-/-) mice.

We studied the role of Semaphorins in the formation of hippocampal connections at embryonic and early postnatal stages. We show that the embryonic entorhinal cortex has a repulsive effect on embryonic hippocampal axons that disappears gradually at postnatal stages. Such chemorepulsion is blocked by Neuropilin-1 and -2 blocking antibodies. However, at perinatal stages, the inner layers of the entorhinal cortex attract CA1 axons. At these stages, Sema3A and Sema3F bind commissural and entorhinal axons. Sema3A and Sema3F repel hippocampal axons at E14-P2, but not at E13. A similar spatiotemporal pattern of chemorepulsion is observed for Sema3A on entorhinal axons, in contrast to Sema3F, which repels these axons only at postnatal ages. Sema3E also repels hippocampal axons but exclusively at E14. We show that Sema3A and Sema3F can induce the collapse of hippocampal growth cones and that membrane-bound Sema3A and Sema3F can guide hippocampal axons in the stripe assay. In sema3A (-/-) mice, the entorhinohippocampal projection is largely normal although single axons innervate aberrantly the stratum radiatum and the hilus. Thus, the chemorepulsion evoked by Sema3A, Sema3E, and Sema3F is dynamically regulated in the developing hippocampal formation.

Age Factors↗
PubMed2002

Pontocerebellar axon guidance: neuropilin-1- and semaphorin 3A-sensitivity gradients across basilar pontine nuclei and semaphorin 3A variation across cerebellum.

To assess the role of semaphorin 3A (Sema3A) and its receptor component neuropilin-1 (Npn-1) in pontocerebellar axon guidance, we compared the distributions of Sema3A, Npn-1, and DiI-labeled pontocerebellar axons in neonatal mouse cerebellum. Between embryonic day 18 and birth there was a large increase in Npn-1 expression in the basilar pontine nuclei (BPN), the major source of pontocerebellar axons. Sema3A expression in cerebellum also increased at this time. In the BPN, Npn-1 and the response of axons to Sema3A were graded with high Npn-1 and Sema3A responsiveness rostrally and lower levels caudally. The Npn-1 gradient was not smooth and cells with higher and lower expression were interspersed. Between birth and postnatal day 5, pontocerebellar axons projected to lobules of the hemispheres, including those with low to moderate levels of Sema3A, but did not enter regions with high levels of Sema3A, including the flocculus and much of the vermis. These results suggest that varying neuropilin levels on BPN axons, which correlated with their varying responses to Sema3A, combined with varying Sema3A levels across cerebellum, may contribute to guiding subsets of BPN axons to their distinct target regions within cerebellum.

Animals↗
PubMed1996

Human semaphorins A(V) and IV reside in the 3p21.3 small cell lung cancer deletion region and demonstrate distinct expression patterns.

Semaphorins and collapsins make up a family of conserved genes that encode nerve growth cone guidance signals. We have identified two additional members of the human semaphorin family [human semaphorin A(V) and human semaphorin IV] in chromosome region 3p21.3, where several small cell lung cancer (SCLC) cell lines exhibit homozygous deletions indicative of a tumor suppressor gene. Human semaphorin A(V) has 86% amino acid homology with murine semaphorin A, whereas semaphorin IV is most closely related to murine semaphorin E, with 50% homology. These semaphorin genes are approximately 70 kb apart flanking two GTP-binding protein genes, GNAI-2 and GNAT-1. In contrast, other human semaphorin gene sequences (human semaphorin III and homologues of murine semaphorins B and C) are not located on chromosome 3. Human semaphorin A(V) is translated in vitro into a 90-kDa protein, which accumulates at the endoplasmic reticulum. The human semaphorin A(V) (3.4-kb mRNA) and IV (3.9- and 2.9-kb mRNAs) genes are expressed abundantly but differentially in a variety of human neural and nonneural tissues. Human semaphorin A(V) was expressed in only 1 out of 23 SCLCs and 7 out of 16 non-SCLCs, whereas semaphorin IV was expressed in 19 out of 23 SCLCs and 13 out of 16 non-SCLCs. Mutational analysis in semaphorin A(V) revealed mutations (germ line in one case) in 3 of 40 lung cancers. Our data suggest the need to determine the function of human semaphorins A(V) and IV in nonneural tissues and their role in the pathogenesis of lung cancer.

Amino Acid Sequence↗
PubMed2002

Injury-induced class 3 semaphorin expression in the rat spinal cord.

In this study we evaluate the expression of all members of the class 3 semaphorins and their receptor components following complete transection and contusion lesions of the adult rat spinal cord. Following both types of lesions the expression of all class 3 semaphorins is induced in fibroblast in the neural scar. The distribution of semaphorin-positive fibroblasts differs markedly in scars formed after transection or contusion lesion. In contusion lesions semaphorin expression is restricted to fibroblasts of the meningeal sheet surrounding the lesion, while after transection semaphorin-positive fibroblast penetrate deep into the center of the lesion. Two major descending spinal cord motor pathways, the cortico- and rubrospinal tract, continue to express receptor components for class 3 semaphorins following injury, rendering them potentially sensitive to scar-derived semaphorins. In line with this we observed that most descending spinal cord fibers were not able to penetrate the semaphorin positive portion of the neural scar formed at the lesion site. These results suggest that the full range of secreted semaphorins contributes to the inhibitory nature of the neural scar and thereby may inhibit successful regeneration in the injured spinal cord. Future studies will focus on the neutralization of class 3 semaphorins, in order to reveal whether this creates a more permissive environment for regeneration of injured spinal cord axons.

Animals↗
PubMed1999

Developmental localization of semaphorin H messenger RNA acting as a collapsing factor on sensory axons in the mouse brain.

Semaphorins/collapsins, a family of genes with a semaphorin domain conserved from insects through to mammals, are believed to be involved in axon guidance during neuronal development. We report the expression patterns of mouse semaphorin messenger RNAs. Among secreted semaphorins, mouse semaphorin H is structurally most similar to semaphorin III/D, the first semaphorin identified as a collapsing factor for sensory axons. However, its expression patterns apparently differ from those of semaphorin III/D. The messenger RNAs are distributed in the brain widely but unevenly during development, in particular, in the main olfactory bulb, hippocampus and pontine nucleus. In the trunk, the expression level is high in mesodermal tissues surrounding the dorsal root ganglia, while it is low in the spinal cord. Moreover, we examined whether this molecule has activity to collapse growth cones of sensory neurons, as well as semaphorin III/D. Mouse semaphorin H collapsed growth cones of sensory neurons of the dorsal root ganglion in a dose-dependent manner, and anti-neuropilin antibodies inhibited this activity. Taken together, these results suggest that mouse semaphorin H can function as a chemorepellent to guide sensory peripheral nerves, most likely via neuropilin as a receptor.

Amino Acid Sequence↗
PubMed1998

Semaphorins act as attractive and repulsive guidance signals during the development of cortical projections.

Members of the semaphorin family have been implicated in mediating axonal guidance in the nervous system by their ability to collapse growth cones and to function as chemorepellents. The present findings show that recombinant Semaphorin D has similar effects on cortical axons and, in addition, inhibits axonal branching. In contrast, semaphorin E acts as an attractive guidance signal for cortical axons. Attractive effects were only observed when growth cones encountered increasing concentrations or a patterned distribution of Semaphorin E, but not when they are exposed to uniform concentrations of this molecule. Specific binding sites for Semaphorin D and Semaphorin E were present on cortical fibers both in vitro and in vivo at the time when corticofugal projections are established. In situ hybridization analysis revealed that the population of cortical neurons used in our experiments express neuropilin-1 and neuropilin-2, which are essential components of receptors for the class III semaphorins. Moreover, semD mRNA was detected in the ventricular zone of the neocortex whereas semE mRNA was restricted to the subventricular zone. Taken together, these results indicate that semaphorins are bifunctional molecules whose effects depend on their spatial distribution. The coordinated expression of different semaphorins, together with their specific activities on cortical axons, suggests that multiple guidance signals contribute to the formation of precise corticofugal pathways.

Animals↗