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O Behar

Publications and source records attributed to O Behar.

10 recordsLinked to original sources
PubMed2000

The development and subsequent elimination of aberrant peripheral axon projections in Semaphorin3A null mutant mice.

Semaphorin3A (previously known as Semaphorin III, Semaphorin D, or collapsin-1) is a member of the semaphorin gene family, many of which have been shown to guide axons during nervous system development. Semaphorin3A has been demonstrated to be a diffusible chemorepulsive molecule for axons of selected neuronal populations in vitro. Analysis of embryogenesis in two independent lines of Semaphorin3A knockout mice support the hypothesis that this molecule is an important guidance signal for neurons of the peripheral nervous system (M. Taniguchi et al., 1997, Neuron 19, 519-530; E. Ulupinar et al., 1999, Mol. Cell. Neurosci. 13, 281-292). Surprisingly, newborn Semaphorin3A null mutant mice exhibit no significant abnormalities (O. Behar et al., 1996, Nature 383, 525-528). In this study we have tested the hypothesis that guidance abnormalities that occurred during early stages of Semaphorin3A null mice development are corrected later in development. We have found that the extensive abnormalities formed during early developmental stages in the peripheral nervous system are largely eliminated by embryonic day 15.5. We demonstrate further that at least in one distinct anatomical location these abnormalities are mainly the result of aberrant projections. In conclusion, these findings suggest the existence of correction mechanisms that eliminate most sensory axon pathfinding errors early in development.

Animals↗
PubMed1999

Semaphorin 3A growth cone collapse requires a sequence homologous to tarantula hanatoxin.

Axonal guidance is key to the formation of neuronal circuitry. Semaphorin 3A (Sema 3A; previously known as semaphorin III, semaphorin D, and collapsin-1), a secreted subtype of the semaphorin family, is an important axonal guidance molecule in vitro and in vivo. The molecular mechanisms of the repellent activity of semaphorins are, however, poorly understood. We have now found that the secreted semaphorins contain a short sequence of high homology to hanatoxin, a tarantula K(+) and Ca(2+) ion channel blocker. Point mutations in the hanatoxin-like sequence of Sema 3A reduce its capacity to repel embryonic dorsal root ganglion axons. Sema 3A growth cone collapse activity is inhibited by hanatoxin, general Ca(2+) channel blockers, a reduction in extracellular or intracellular Ca(2+), and a calmodulin inhibitor, but not by K(+) channel blockers. Our data support an important role for Ca(2+) in mediating the Sema 3A response and suggest that Sema 3A may produce its effects by causing the opening of Ca(2+) channels.

Amino Acid Sequence↗
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↗
PubMed1999

PhosphoCREB and CREM/ICER: positive and negative regulation of proenkephalin gene expression in the paraventricular nucleus of the hypothalamus.

In the hypothalamic paraventricular nucleus (PVN), the proenkephalin gene may be upregulated by lipopolysaccharide (LPS) and downregulated by the GABA-A agonist muscimol. Candidate transcription factors regulating the proenkephalin gene in opposite directions are cAMP-response-element-binding protein (CREB) (when phosphorylated, a positive regulator) and cAMP-responsive modulatory inducible cAMP early repressor (CREM/ICER) (a negative regulator). Our results demonstrate that CREM alpha,beta,gamma transcripts and ICER are induced in the PVN by LPS and remain elevated for periods of up to 12 h. PhosphoCREB is elevated after LPS administration, peaking at 8 h, but remaining elevated over control levels at 12 h. Phospho-CREB induction by LPS is also seen in primary hypothalamic cultures. Cotransfection of ICER with ENK-CAT12 into primary hypothalamic cultures produced a decrease in chloramphenicol acetyl transferase (CAT) levels following cAMP or LPS stimulation. PhosphoCREB is downregulated and CREM/ICER is upregulated in the PVN by muscimol, suggesting that the regulation of these transcription factors may underlie the inhibitory effect of muscimol on target genes in the PVN.

1-Methyl-3-isobutylxanthine↗
PubMed1997

A novel transmembrane semaphorin can bind c-src.

The semaphorins/collapsins constitute a family of genes unified by the presence of a "semaphorin domain" which has been conserved through metazoan evolution. The semaphorin family comprises both secreted and transmembrane molecules and is thought to be made up of ligands for as yet unidentified receptors. The functions are not known, with the exception of those of sema III (also referred as sem D and collapsin 1), D-sema I, and D-sema II, which have been shown to be involved in axonal pathfinding. Here report the identification of a mouse semaphorin cDNA, termed Sema VIb. Although Sema VIb contains the extracellular semaphorin domain, it lacks the immunoglobulin domain or thrombospondin repeats which are present in other described vertebrate (but not invertebrate) transmembrane semaphorins. During development Sema VIb mRNA is expressed in subregions of the nervous system and is particularly prominent in muscle. In adulthood, Sema VIb mRNA is expressed ubiquitously. The cytoplasmic domain of Sema VIb contains several proline-rich potential SH3 domain binding sites. Using an in vitro binding assay, we show that Sema VIb binds specifically the SH3 domain of the protooncogene c-src. In transfected COS cells Sema VIb coimmunoprecipitates with c-src. These results, along with our evidence that Sema VIb can form dimers, suggests that the semaphorin family not only serves as ligands but may include members, especially those which are transmembrane, which serve as receptors, triggering intracellular signaling via an src-related cascade.

Amino Acid Sequence↗
PubMed1996

Semaphorin III is needed for normal patterning and growth of nerves, bones and heart.

The expression patterns of the recently discovered family of semaphorin genes suggests that they have widespread roles in embryonic development. Some seem to guide neuronal growth cones, but otherwise their functions are unknown. Semaphorin III is a membrane-associated secreted protein with a developmentally dynamic pattern of expression, including particular domains of the nervous system, the borders of developing bones, and the heart. In vitro, semaphorin III causes growth-cone collapse, and repels cutaneous sensory axons from the ventral spinal cord. Mutants in the Drosophila gene semaII, which encodes a related semaphorin, die after eclosion, but no responsible abnormality is evident. We have generated mice mutant in the semaIII gene by homologous recombination. Here we show that in the mutants, some sensory axons project into inappropriate regions of the spinal cord where semaIII is normally expressed. The cerebral cortex of homozygous mutant mice shows a paucity of neuropil and abnormally oriented neuronal processes, especially of the large pyramidal neurons. Certain embryonic bones and cartilaginous structures develop abnormally, with vertebral fusions and partial rib duplications. The few mice that survive more than a few days postnatally manifest pronounced and selective hypertrophy of the right ventricle of the heart and dilation of the right atrium. Thus, semaphorin III might serve as a signal that restrains growth in several developing organs.

Animals↗
PubMed1996

Molecular characterization of immune derived proenkephalin mRNA and the involvement of the adrenergic system in its expression in rat lymphoid cells.

Proenkephalin (PENK), a classically defined opioid gene, was originally thought to be expressed almost exclusively in the mature nervous and neuroendocrine systems. In the last few years, it was demonstrated, however, that significant levels of PENK mRNA and PENK-derived peptides are transiently expressed in cells of the immune system. Very little is known about the molecular mechanisms regulating this transient expression. In order to investigate those mechanisms, we examined the in vivo expression of PENK mRNA in mesenteric lymph nodes after exposing rats to lipopolysaccharide. In the present study we demonstrate that: (i) promoter usage and splicing of PENK mRNA function similarly in mesenteric lymph nodes as in neural cells; (2) PENK expression in mesenteric lymph nodes is modulated by adrenaline via adrenergic receptors; and (3) the adrenergic system participates in the modulation of the LPS induced PENK mRNA expression. These results provide more evidence for the involvement of opioids in neuro-immune interactions.

Adrenergic Agonists↗
PubMed1994

Lipopolysaccharide induces proenkephalin gene expression in rat lymph nodes and adrenal glands.

The proenkephalin gene encodes a family of neuropeptides that was originally identified in brain tissue and adrenal glands. Recently, it was shown that proenkephalin is also expressed in cultured lymphoid cells. To elucidate the physiological significance of this expression, we examined the in vivo expression of proenkephalin in lymphoid tissues. We show here that exposing rats to the endotoxin lipopolysaccharide induces an intense and transient expression of proenkephalin in adrenal glands and lymph nodes. By using combined in situ hybridization and immunohistochemistry on tissue slices, we identified proenkephalin expression in macrophages located within the lymph nodes and in chromaffin cells within the adrenal glands. This in vivo expression of proenkephalin was enhanced by adrenaline. The present observations demonstrate that the immune system is a site of significant expression of proenkephalin and provide a basis for neuroimmune interactions.

Adrenal Glands↗
PubMed1989

Regulated expression of proenkephalin A in normal lymphocytes.

The expression of proenkephalin A (PEA), a neuropeptide-encoding gene, was examined in normal rat lymphocytes. With the use of Northern blot hybridization analysis of total RNA, PEA mRNA was found in normal cells derived from spleen, lymph nodes, and bone marrow. Cell sorting of the two main fractions of B and T cells derived from the spleen revealed that PEA is expressed in normal B cells (sIg+). The expression of PEA mRNA was markedly enhanced after a short incubation (3 h) of cells with LPS or Salmonella typhimurium. This was not the case when these cells were incubated with Con A during the same period of time; whereas, in thymocytes the presence of PEA mRNA was exclusively dependent upon mitogenic stimulus (Con A) and could be detected after 24 h of in vitro incubation. Extracts of cells were also found to contain immune reactive enkephalins, indicating that the PEA mRNA is translated. These results support the concept that neuropeptides, such as enkephalins, have a role in the modulation of the immune response and may participate in the bidirectional communication between the nervous and immune systems.

Animals↗