The glycosylphosphatidyl inositol-anchored adhesion molecule F3/contactin is required for surface transport of paranodin/contactin-associated protein (caspr).
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Paranodin/contactin-associated protein (caspr) is a transmembrane glycoprotein of the neurexin superfamily that is highly enriched in the paranodal regions of myelinated axons. We have investigated the role of its association with F3/contactin, a glycosylphosphatidyl inositol (GPI)-anchored neuronal adhesion molecule of the Ig superfamily. Paranodin was not expressed at the cell surface when transfected alone in CHO or neuroblastoma cells. Cotransfection with F3 resulted in plasma membrane delivery of paranodin, as analyzed by confocal microscopy and cell surface biotinylation. The region that mediates association with paranodin was mapped to the Ig domains of F3 by coimmunoprecipitation experiments. The association of paranodin with F3 allowed its recruitment to Triton X-100-insoluble microdomains. The GPI anchor of F3 was necessary, but not sufficient for surface expression of paranodin. F3-Ig, a form of F3 deleted of the fibronectin type III (FNIII) repeats, although GPI-linked and expressed at the cell surface, was not recovered in the microdomain fraction and was unable to promote cell surface targeting of paranodin. Thus, a cooperative effect between the GPI anchor, the FNIII repeats, and the Ig regions of F3 is required for recruitment of paranodin into lipid rafts and its sorting to the plasma membrane. (+info)
The normal patched allele is expressed in medulloblastomas from mice with heterozygous germ-line mutation of patched.
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Defects in a developmental signaling pathway involving mammalian homologues of the Drosophila segment polarity gene, patched (ptc) and its ligand, sonic hedgehog (shh), contribute to tumor formation in several tissues. Recently, a subset of medulloblastoma, the most common malignant brain tumor in children, was found to contain somatic mutations in the human ptc gene. In addition, basal cell nevus syndrome (BCNS), or Gorlin syndrome, which is characterized by developmental anomalies and a predisposition to skin and nervous system malignancies, is associated with germ-line mutation of ptc. Targeted disruption of both alleles of ptc in mice results in embryonic lethality. However, ptc+/- mice survive and develop spontaneous cerebellar brain tumors, suggesting that ptc may function as a tumor suppressor gene. Therefore, we investigated ptc+/-mice as a model for human medulloblastoma. We report that 14% of ptc+/- mice develop central nervous system tumors in the posterior fossa by 10 months of age, with peak tumor incidence occurring between 16 and 24 weeks of age. The tumors exhibited several characteristics of human medulloblastoma, including expression of intermediate filament proteins specific for neurons and glia. Full-length ptc mRNA was present in all tumors analyzed, indicating that there was no loss of heterozygosity at the ptc locus. Nucleotide sequence of ptc mRNA from four tumors failed to identify any mutations. However, a comparison of the normal ptc sequence from C57BL/6 and 129Sv mice did reveal several polymorphisms. High levels of glil mRNA and protein were detected in the tumors, suggesting that the shh/ptc pathway was activated despite the persistence of ptc expression. These data indicate that haploinsufficiency of ptc is sufficient to promote oncogenesis in the central nervous system. (+info)
An essential role of the neuronal cell adhesion molecule contactin in development of the Xenopus primary sensory system.
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Contactin is a glycosylphosphatidylinositol-anchored immunoglobulin-like neuronal cell adhesion molecule that has been implicated in cellular interaction during development of the vertebrate central nervous system. Here we report evidence for an essential role of contactin in development of the Xenopus nervous system. Contactin mRNA is detectable by in situ hybridization in subsets of neurons in the brain, primary sensory neurons in the spinal cord, and cells along the trigeminal nerves of tailbud embryos. Contactin immunoreactivities preferentially distribute on axon tracts of the brain, the spinal cord, and the trigeminal sensory nerves. Most prominently, cell bodies and peripheral and spinal axons of primary sensory neurons, Rohon-Beard (RB) cells, are strongly contactin positive. Injection of the contactin overexpression vector into one blastomere of two-cell stage embryos leads to misdirected elongation of the peripheral axons of RB neurons in the injected half. Overexpression of antisense transcript causes depletion of contactin mRNA accumulation and abnormal development of RB neurons. In 52.3% of the injected embryos, RB neurons decrease in number and their peripheral axons in dorsal lateral tracts are defasciculated. These results demonstrate that contactin plays an essential role in development of the Xenopus primary sensory system. (+info)
Differential expression of two adhesion molecules of the immunoglobulin superfamily, F3 and polysialylated NCAM, in hypothalamic magnocellular neurones capable of plasticity.
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The adult hypothalamo-neurohypophysial system undergoes activity-dependent, reversible morphological changes which result in reduced astrocytic coverage of its neurones and an increase in their synaptic contacts. Our recent observations show that neurones and glia of the hypothalamo-neurohypophysial system continue to express 'embryonic' molecular features which may underlie their capacity to undergo such plasticity. These include expression of cell surface molecules like the glycosyl phosphatidyl inositol (GPI)-linked glycoprotein F3, which intervenes in axonal outgrowth, and the polysialylated isoform of the neural cell adhesion molecule (PSA-NCAM), which reduces cell adhesion and promotes dynamic cell interactions. F3 is colocalised with vasopressin and oxytocin hormones in neurosecretory granules and follows an activity-dependent, regulated pathway for surface expression on neurohypophysial axons. In contrast, PSA-NCAM appears to follow a constitutive pathway, independent of the activity of the hypothalamo-neurohypophysial system, for expression on axonal and glial surfaces, in the hypothalamic magnocellular nuclei and in the neurohypophysis. The role of F3 remains to be determined but in view of its presumptive functions during development, we propose that it promotes remodelling of neurosecretory terminals. On the other hand, we provide direct evidence that surface expression of PSA on NCAM is essential to morphological plasticity since its specific enzymatic degradation in vivo inhibited the neuronal-glial and synaptic changes normally induced by stimulation of secretion from the hypothalamo-neurohypophysial system. (+info)
Neuronal basic helix-loop-helix proteins (NEX and BETA2/Neuro D) regulate terminal granule cell differentiation in the hippocampus.
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The transcription factors neuronal helix-loop-helix protein (NEX)/mammalian atonal homolog 2 (Math-2), BETA2/neuronal determination factor (NeuroD), and NeuroD-related factor (NDRF)/NeuroD2 comprise a family of Drosophila atonal-related basic helix-loop-helix (bHLH) proteins with highly overlapping expression in the developing forebrain. The ability of BETA2/NeuroD and NDRF to convert ectodermal cells into neurons after mRNA injection into Xenopus oocytes suggested a role in specifying neuronal cell fate. However, neuronal bHLH genes are largely transcribed in CNS neurons, which are fully committed. Here we analyze a defect in mice lacking BETA2/NeuroD, and in NEX*BETA2/NeuroD double mutants, demonstrating that bHLH proteins are required in vivo for terminal neuronal differentiation. Most strikingly, presumptive granule cells of the dentate gyrus are generated but fail to mature, lack normal sodium currents, and show little dendritic arborization. Long-term hippocampal slice cultures demonstrate secondary alterations of entorhinal and commissural/associational projections. The primary developmental arrest appears to be restricted to granule cells in which an autoregulatory system involving all three neuronal bHLH genes has failed. (+info)
A direct interaction of axonin-1 with NgCAM-related cell adhesion molecule (NrCAM) results in guidance, but not growth of commissural axons.
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An interaction of growth cone axonin-1 with the floor-plate NgCAM-related cell adhesion molecule (NrCAM) was shown to play a crucial role in commissural axon guidance across the midline of the spinal cord. We now provide evidence that axonin-1 mediates a guidance signal without promoting axon elongation. In an in vitro assay, commissural axons grew preferentially on stripes coated with a mixture of NrCAM and NgCAM. This preference was abolished in the presence of anti-axonin-1 antibodies without a decrease in neurite length. Consistent with these findings, commissural axons in vivo only fail to extend along the longitudinal axis when both NrCAM and NgCAM interactions, but not when axonin-1 and NrCAM or axonin-1 and NgCAM interactions, are perturbed. Thus, we conclude that axonin-1 is involved in guidance of commissural axons without promoting their growth. (+info)
The reelin receptor ApoER2 recruits JNK-interacting proteins-1 and -2.
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Correct positioning of neurons during embryonic development of the brain depends, among other processes, on the proper transmission of the reelin signal into the migrating cells via the interplay of its receptors with cytoplasmic signal transducers. Cellular components of this signaling pathway characterized to date are cell surface receptors for reelin like apolipoprotein E receptor 2 (ApoER2), very low density lipoprotein receptor (VLDLR), and cadherin-related neuronal receptors, and intracellular components like Disabled-1 and the nonreceptor tyrosine kinase Fyn, which bind to the intracellular domains of the ApoER2 and VLDL receptor or of cadherin-related neuronal receptors, respectively. Here we show that ApoER2, but not VLDLR, also binds the family of JNK-interacting proteins (JIPs), which act as molecular scaffolds for the JNK-signaling pathway. The ApoER2 binding domain on JIP-2 does not overlap with the binding sites for MLK3, MKK7, and JNK. These results suggest that ApoER2 is able to assemble a multiprotein complex containing Disabled-1 and JIPs, together with their binding partners, to the cell surface of neurons. This complex might participate in ApoER2-specific reelin signaling and thus would explain the different phenotype of mice lacking the ApoER2 from that of VLDLR-deficient mice. (+info)
Regulation of neuronal cell adhesion molecule expression by NF-kappa B.
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The neuronal cell adhesion molecule (NCAM) is a key mediator of structural plasticity in the central nervous system, but the mechanisms that control its expression are unknown. Equally, although the transcription factor NF-kappaB is present in the brain, few NF-kappaB-regulated genes relevant for central nervous system function have been identified. We have previously demonstrated that NF-kappaB is activated in neuronal cultures treated with kainic acid or nitric oxide. We show here that kainic acid or nitric oxide also increase the levels of NCAM mRNA and protein in neurons and that this induction of NCAM expression is sensitive to dexamethasone and to antisense, but not missense, oligonucleotides designed to suppress NF-kappaB synthesis. Nitric oxide also stimulates protein binding to an NF-kappaB site in the promoter of the NCAM gene. This indicates that NF-kappaB, which has recently been implicated in synaptic plasticity and also in the etiology of neurodegenerative disease, plays a crucial role in the activity-dependent regulation of NCAM gene expression. In addition, since both NCAM and NF-kappaB are present in the post-synaptic density, this represents a route allowing direct communication between the synapse and the nucleus. (+info)