G2Cdb::Gene report

Gene id
Gene symbol
Nfasc (MGI)
Mus musculus
G00001810 (Homo sapiens)

Databases (8)

ENSMUSG00000026442 (Ensembl mouse gene)
269116 (Entrez Gene)
978 (G2Cdb plasticity & disease)
Gene Expression
MGI:104753 (Allen Brain Atlas)
269116 (Genepaint)
609145 (OMIM)
Marker Symbol
MGI:104753 (MGI)
Protein Sequence
Q810U3 (UniProt)

Literature (26)

Pubmed - other

  • A critical role for Neurofascin in regulating action potential initiation through maintenance of the axon initial segment.

    Zonta B, Desmazieres A, Rinaldi A, Tait S, Sherman DL, Nolan MF and Brophy PJ

    Centre for Neuroregeneration, University of Edinburgh, Edinburgh, UK.

    The axon initial segment (AIS) is critical for the initiation and propagation of action potentials. Assembly of the AIS requires interactions between scaffolding molecules and voltage-gated sodium channels, but the molecular mechanisms that stabilize the AIS are poorly understood. The neuronal isoform of Neurofascin, Nfasc186, clusters voltage-gated sodium channels at nodes of Ranvier in myelinated nerves: here, we investigate its role in AIS assembly and stabilization. Inactivation of the Nfasc gene in cerebellar Purkinje cells of adult mice causes rapid loss of Nfasc186 from the AIS but not from nodes of Ranvier. This causes AIS disintegration, impairment of motor learning and the abolition of the spontaneous tonic discharge typical of Purkinje cells. Nevertheless, action potentials with a modified waveform can still be evoked and basic motor abilities remain intact. We propose that Nfasc186 optimizes communication between mature neurons by anchoring the key elements of the adult AIS complex.

    Funded by: Medical Research Council: G0301172, G0501216; Wellcome Trust

    Neuron 2011;69;5;945-56

  • Nodes of Ranvier act as barriers to restrict invasion of flanking paranodal domains in myelinated axons.

    Thaxton C, Pillai AM, Pribisko AL, Dupree JL and Bhat MA

    Department of Cell and Molecular Physiology, University of North Carolina School of Medicine, Chapel Hill, Chapel Hill, NC 27599-7545, USA.

    Accumulation of voltage-gated sodium (Na(v)) channels at nodes of Ranvier is paramount for action potential propagation along myelinated fibers, yet the mechanisms governing nodal development, organization, and stabilization remain unresolved. Here, we report that genetic ablation of the neuron-specific isoform of Neurofascin (Nfasc(NF¹⁸⁶)) in vivo results in nodal disorganization, including loss of Na(v) channel and ankyrin-G (AnkG) enrichment at nodes in the peripheral nervous system (PNS) and central nervous system (CNS). Interestingly, the presence of paranodal domains failed to rescue nodal organization in the PNS and the CNS. Most importantly, using ultrastructural analysis, we demonstrate that the paranodal domains invade the nodal space in Nfasc(NF¹⁸⁶) mutant axons and occlude node formation. Our results suggest that Nfasc(NF¹⁸⁶)-dependent assembly of the nodal complex acts as a molecular boundary to restrict the movement of flanking paranodal domains into the nodal area, thereby facilitating the stereotypic axonal domain organization and saltatory conduction along myelinated axons.

    Funded by: NIGMS NIH HHS: GM063074, R01 GM063074, R01 GM063074-09; NINDS NIH HHS: NS050356, R01 NS050356, R01 NS050356-05

    Neuron 2011;69;2;244-57

  • A high-resolution anatomical atlas of the transcriptome in the mouse embryo.

    Diez-Roux G, Banfi S, Sultan M, Geffers L, Anand S, Rozado D, Magen A, Canidio E, Pagani M, Peluso I, Lin-Marq N, Koch M, Bilio M, Cantiello I, Verde R, De Masi C, Bianchi SA, Cicchini J, Perroud E, Mehmeti S, Dagand E, Schrinner S, Nürnberger A, Schmidt K, Metz K, Zwingmann C, Brieske N, Springer C, Hernandez AM, Herzog S, Grabbe F, Sieverding C, Fischer B, Schrader K, Brockmeyer M, Dettmer S, Helbig C, Alunni V, Battaini MA, Mura C, Henrichsen CN, Garcia-Lopez R, Echevarria D, Puelles E, Garcia-Calero E, Kruse S, Uhr M, Kauck C, Feng G, Milyaev N, Ong CK, Kumar L, Lam M, Semple CA, Gyenesei A, Mundlos S, Radelof U, Lehrach H, Sarmientos P, Reymond A, Davidson DR, Dollé P, Antonarakis SE, Yaspo ML, Martinez S, Baldock RA, Eichele G and Ballabio A

    Telethon Institute of Genetics and Medicine, Naples, Italy.

    Ascertaining when and where genes are expressed is of crucial importance to understanding or predicting the physiological role of genes and proteins and how they interact to form the complex networks that underlie organ development and function. It is, therefore, crucial to determine on a genome-wide level, the spatio-temporal gene expression profiles at cellular resolution. This information is provided by colorimetric RNA in situ hybridization that can elucidate expression of genes in their native context and does so at cellular resolution. We generated what is to our knowledge the first genome-wide transcriptome atlas by RNA in situ hybridization of an entire mammalian organism, the developing mouse at embryonic day 14.5. This digital transcriptome atlas, the Eurexpress atlas (http://www.eurexpress.org), consists of a searchable database of annotated images that can be interactively viewed. We generated anatomy-based expression profiles for over 18,000 coding genes and over 400 microRNAs. We identified 1,002 tissue-specific genes that are a source of novel tissue-specific markers for 37 different anatomical structures. The quality and the resolution of the data revealed novel molecular domains for several developing structures, such as the telencephalon, a novel organization for the hypothalamus, and insight on the Wnt network involved in renal epithelial differentiation during kidney development. The digital transcriptome atlas is a powerful resource to determine co-expression of genes, to identify cell populations and lineages, and to identify functional associations between genes relevant to development and disease.

    Funded by: Medical Research Council: MC_U127527203; Telethon: TGM11S03

    PLoS biology 2011;9;1;e1000582

  • In vivo deletion of immunoglobulin domains 5 and 6 in neurofascin (Nfasc) reveals domain-specific requirements in myelinated axons.

    Thaxton C, Pillai AM, Pribisko AL, Labasque M, Dupree JL, Faivre-Sarrailh C and Bhat MA

    Department of Cell and Molecular Physiology, and UNC-Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7545, USA.

    The formation of paranodal axo-glial junctions is critical for the rapid and efficient propagation of nerve impulses. Genetic ablation of genes encoding the critical paranodal proteins Caspr, contactin (Cont), and the myelinating glia-specific isoform of Neurofascin (Nfasc(NF155)) results in the disruption of the paranodal axo-glial junctions, loss of ion channel segregation, and impaired nerve conduction, but the mechanisms regulating their interactions remain elusive. Here, we report that loss of immunoglobulin (Ig) domains 5 and 6 in Nfasc(NF155) in mice phenocopies complete ablation of Nfasc(NF155). The mutant mice lack paranodal septate junctions, resulting in the diffusion of Caspr and Cont from the paranodes, and redistribution of the juxtaparanodal potassium channels toward the nodes. Although critical for Nfasc(NF155) function, we find that Ig5-6 are dispensable for nodal Nfasc(NF186) function. Moreover, in vitro binding assays using Ig5-6 deletion constructs reveal their importance for the association of Nfasc(NF155) with Cont. These findings provide the first molecular evidence demonstrating domain-specific requirements controlling the association of the paranodal tripartite complex in vivo. Our studies further emphasize that in vivo structure/function analysis is necessary to define the unique protein-protein interactions that differentially regulate the functions of Neurofascins during axonal domain organization.

    Funded by: NIGMS NIH HHS: GM063074, R01 GM063074, R01 GM063074-08; NINDS NIH HHS: NS050356, R01 NS050356, R01 NS050356-05

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2010;30;14;4868-76

  • A glial signal consisting of gliomedin and NrCAM clusters axonal Na+ channels during the formation of nodes of Ranvier.

    Feinberg K, Eshed-Eisenbach Y, Frechter S, Amor V, Salomon D, Sabanay H, Dupree JL, Grumet M, Brophy PJ, Shrager P and Peles E

    Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.

    Saltatory conduction requires high-density accumulation of Na(+) channels at the nodes of Ranvier. Nodal Na(+) channel clustering in the peripheral nervous system is regulated by myelinating Schwann cells through unknown mechanisms. During development, Na(+) channels are first clustered at heminodes that border each myelin segment, and later in the mature nodes that are formed by the fusion of two heminodes. Here, we show that initial clustering of Na(+) channels at heminodes requires glial NrCAM and gliomedin, as well as their axonal receptor neurofascin 186 (NF186). We further demonstrate that heminodal clustering coincides with a second, paranodal junction (PNJ)-dependent mechanism that allows Na(+) channels to accumulate at mature nodes by restricting their distribution between two growing myelin internodes. We propose that Schwann cells assemble the nodes of Ranvier by capturing Na(+) channels at heminodes and by constraining their distribution to the nodal gap. Together, these two cooperating mechanisms ensure fast and efficient conduction in myelinated nerves.

    Funded by: Medical Research Council: G0301172; NINDS NIH HHS: NS17965, NS50220, R01 NS017965, R01 NS050220, R01 NS050220-05

    Neuron 2010;65;4;490-502

  • Novel forms of neurofascin 155 in the central nervous system: alterations in paranodal disruption models and multiple sclerosis.

    Pomicter AD, Shroff SM, Fuss B, Sato-Bigbee C, Brophy PJ, Rasband MN, Bhat MA and Dupree JL

    Department of Anatomy and Neurobiology, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.

    Stability of the myelin-axon unit is achieved, at least in part, by specialized paranodal junctions comprised of the neuronal heterocomplex of contactin and contactin-associated protein and the myelin protein neurofascin 155. In multiple sclerosis, normal distribution of these proteins is altered, resulting in the loss of the insulating myelin and consequently causing axonal dysfunction. Previously, this laboratory reported that mice lacking the myelin-enriched lipid sulphatide are characterized by a progressive deterioration of the paranodal structure. Here, it is shown that this deterioration is preceded by significant loss of neurofascin 155 clustering at the myelin paranode. Interestingly, prolonged electrophoretic separation revealed the existence of two neurofascin 155 bands, neurofascin 155 high and neurofascin 155 low, which are readily observed following N-linked deglycosylation. Neurofascin 155 high is observed at 7 days of age and reaches peak expression at one month of age, while neurofascin 155 low is first observed at 14 days of age and constantly increases until 5 months of age. Studies using conditional neurofascin knockout mice indicated that neurofascin 155 high and neurofascin 155 low are products of the neurofascin gene and are exclusively expressed by oligodendrocytes within the central nervous system. Neurofascin 155 high is a myelin paranodal protein while the distribution of neurofascin 155 low remains to be determined. While neurofascin 155 high levels are significantly reduced in the sulphatide null mice at 15 days, 30 days and 4 months of age, neurofascin 155 low levels remain unaltered. Although maintained at normal levels, neurofascin 155 low is incapable of preserving paranodal structure, thus indicating that neurofascin 155 high is required for paranodal stability. Additionally, comparisons between neurofascin 155 high and neurofascin 155 low in human samples revealed a significant alteration, specifically in multiple sclerosis plaques.

    Funded by: Medical Research Council: G0301172; NIGMS NIH HHS: GM063074; NINDS NIH HHS: NS066186

    Brain : a journal of neurology 2010;133;Pt 2;389-405

  • Analysis of non-canonical fibroblast growth factor receptor 1 (FGFR1) interaction reveals regulatory and activating domains of neurofascin.

    Kirschbaum K, Kriebel M, Kranz EU, Pötz O and Volkmer H

    Department of Molecular Biology, Naturwissenschaftliches und Medizinisches Institut an der Universität Tübingen, Markwiesenstrasse 55, 72770 Reutlingen, Germany

    Fibroblast growth factor receptors (FGFRs) are important for many different mechanisms, including cell migration, proliferation, differentiation, and survival. Here, we show a new link between FGFR1 and the cell adhesion molecule neurofascin, which is important for neurite outgrowth. After overexpression in HEK293 cells, embryonal neurofascin isoform NF166 was able to associate with FGFR1, whereas the adult isoform NF186, differing from NF166 in additional extracellular sequences, was deficient. Pharmacological inhibitors and overexpression of dominant negative components of the FGFR signaling pathway pointed to the activation of FGFR1 after association with neurofascin in neurite outgrowth assays in chick tectal neurons and rat PC12-E2 cells. Both extra- and intracellular domains of embryonal neurofascin isoform NF166 were able to form complexes with FGFR1 independently. However, the cytosolic domain was both necessary and sufficient for the activation of FGFR1. Cytosolic serine residues 56 and 100 were shown to be essential for the neurite outgrowth-promoting activity of neurofascin, whereas both amino acid residues were dispensable for FGFR1 association. In conclusion, the data suggest a neurofascin intracellular domain, which activates FGFR1 for neurite outgrowth, whereas the extracellular domain functions as an additional, regulatory FGFR1 interaction domain in the course of development.

    The Journal of biological chemistry 2009;284;42;28533-42

  • Targeted inactivation of a developmentally regulated neural plectin isoform (plectin 1c) in mice leads to reduced motor nerve conduction velocity.

    Fuchs P, Zörer M, Reipert S, Rezniczek GA, Propst F, Walko G, Fischer I, Bauer J, Leschnik MW, Lüscher B, Thalhammer JG, Lassmann H and Wiche G

    Department of Biochemistry and Cell Biology, Max F Perutz Laboratories, University of Vienna, 1030 Vienna, Austria.

    Cytolinker proteins stabilize cells mechanically, regulate cytoskeleton dynamics, and provide scaffolds for signaling molecules. For plectin, the prototype of these proteins, an unusual diversity of isoforms has been reported, which show distinct expression patterns, subcellular localizations, and functions. Plectin has been shown to have important functions in skin and muscle, but little is known about its role in neural cells. To address this issue, we generated two knock-out mouse lines, one which was selectively lacking plectin 1c (P1c), the major isoform expressed in neural cells, and another in which plectin was conditionally deleted in neuronal precursor cells. Using isoform-specific antibodies, we found P1c to be expressed late in development and to associate with postsynaptic dendrites of central nervous system neurons, motorneurons of spinal cord, sciatic nerve axons, and Schwann cells. Motor nerve conduction velocity was found significantly reduced in sciatic nerve from P1c-deficient as well as from conditional knock-out mice. This defect was traceable to an increased number of motor nerve fibers with small cross-sectional areas; the thicknesses of axons and of myelin sheaths were unaffected. This is the first report demonstrating an important role of plectin in a major nerve function.

    Funded by: Austrian Science Fund FWF: P 17862, P 20744

    The Journal of biological chemistry 2009;284;39;26502-9

  • Spatiotemporal ablation of myelinating glia-specific neurofascin (Nfasc NF155) in mice reveals gradual loss of paranodal axoglial junctions and concomitant disorganization of axonal domains.

    Pillai AM, Thaxton C, Pribisko AL, Cheng JG, Dupree JL and Bhat MA

    Department of Cell and Molecular Physiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7545, USA.

    The evolutionary demand for rapid nerve impulse conduction led to the process of myelination-dependent organization of axons into distinct molecular domains. These domains include the node of Ranvier flanked by highly specialized paranodal domains where myelin loops and axolemma orchestrate the axoglial septate junctions. These junctions are formed by interactions between a glial isoform of neurofascin (Nfasc(NF155)) and axonal Caspr and Cont. Here we report the generation of myelinating glia-specific Nfasc(NF155) null mouse mutants. These mice exhibit severe ataxia, motor paresis, and death before the third postnatal week. In the absence of glial Nfasc(NF155), paranodal axoglial junctions fail to form, axonal domains fail to segregate, and myelinated axons undergo degeneration. Electrophysiological measurements of peripheral nerves from Nfasc(NF155) mutants revealed dramatic reductions in nerve conduction velocities. By using inducible PLP-CreER recombinase to ablate Nfasc(NF155) in adult myelinating glia, we demonstrate that paranodal axoglial junctions disorganize gradually as the levels of Nfasc(NF155) protein at the paranodes begin to drop. This coincides with the loss of the paranodal region and concomitant disorganization of the axonal domains. Our results provide the first direct evidence that the maintenance of axonal domains requires the fence function of the paranodal axoglial junctions. Together, our studies establish a central role for paranodal axoglial junctions in both the organization and the maintenance of axonal domains in myelinated axons.

    Funded by: NIGMS NIH HHS: GM63074, R01 GM063074, R01 GM063074-08; NINDS NIH HHS: 5P30NS047463, NS050356, P30 NS047463, R01 NS050356, R01 NS050356-04

    Journal of neuroscience research 2009;87;8;1773-93

  • Glial and neuronal isoforms of Neurofascin have distinct roles in the assembly of nodes of Ranvier in the central nervous system.

    Zonta B, Tait S, Melrose S, Anderson H, Harroch S, Higginson J, Sherman DL and Brophy PJ

    Centre for Neuroscience Research, Royal Dick School of Veterinary Studies, University of Edinburgh, Edinburgh EH9 1QH, Scotland, UK.

    Rapid nerve impulse conduction in myelinated axons requires the concentration of voltage-gated sodium channels at nodes of Ranvier. Myelin-forming oligodendrocytes in the central nervous system (CNS) induce the clustering of sodium channels into nodal complexes flanked by paranodal axoglial junctions. However, the molecular mechanisms for nodal complex assembly in the CNS are unknown. Two isoforms of Neurofascin, neuronal Nfasc186 and glial Nfasc155, are components of the nodal and paranodal complexes, respectively. Neurofascin-null mice have disrupted nodal and paranodal complexes. We show that transgenic Nfasc186 can rescue the nodal complex when expressed in Nfasc(-/-) mice in the absence of the Nfasc155-Caspr-Contactin adhesion complex. Reconstitution of the axoglial adhesion complex by expressing transgenic Nfasc155 in oligodendrocytes also rescues the nodal complex independently of Nfasc186. Furthermore, the Nfasc155 adhesion complex has an additional function in promoting the migration of myelinating processes along CNS axons. We propose that glial and neuronal Neurofascins have distinct functions in the assembly of the CNS node of Ranvier.

    Funded by: Medical Research Council: G0301172; Multiple Sclerosis Society: 669; Wellcome Trust

    The Journal of cell biology 2008;181;7;1169-77

  • Alpha6beta4 integrin and dystroglycan cooperate to stabilize the myelin sheath.

    Nodari A, Previtali SC, Dati G, Occhi S, Court FA, Colombelli C, Zambroni D, Dina G, Del Carro U, Campbell KP, Quattrini A, Wrabetz L and Feltri ML

    Department of Biological and Technological Research, San Raffaele Scientific Institute, 20132 Milan, Italy.

    Schwann cells integrate signals deriving from the axon and the basal lamina to myelinate peripheral nerves. Integrin alpha6beta4 is a laminin receptor synthesized by Schwann cells and displayed apposed to the basal lamina. alpha6beta4 integrin expression in Schwann cells is induced by axons at the onset of myelination, and rises in adulthood. The beta4 chain has a uniquely long cytoplasmic domain that interacts with intermediate filaments such as dystonin, important in peripheral myelination. Furthermore, alpha6beta4 integrin binds peripheral myelin protein 22, whose alteration causes the most common demyelinating hereditary neuropathy. All these data suggest a role for alpha6beta4 integrin in peripheral nerve myelination. Here we show that ablating alpha6beta4 integrin specifically in Schwann cells of transgenic mice does not affect peripheral nerve development, myelin formation, maturation, or regeneration. However, consistent with maximal expression in adult nerves, alpha6beta4 integrin-null myelin is more prone to abnormal folding with aging. When the laminin receptor dystroglycan is also ablated, major folding abnormalities occur, associated with acute demyelination in some peripheral nervous system districts. These data indicate that, similar to its role in skin, alpha6beta4 integrin confers stability to myelin in peripheral nerves.

    Funded by: NINDS NIH HHS: R01 NS045630, R01 NS045630-06, R01 NS045630-09, R01 NS055256, R01 NS055256-01, R01 NS055256-02, R01 NS055256-03, R01-NS045630, R01-NS055256, U54 NS053672, U54-NS053672; Telethon: GGP04019, GGP07100, GTF07004

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2008;28;26;6714-9

  • Expression and function of junctional adhesion molecule-C in myelinated peripheral nerves.

    Scheiermann C, Meda P, Aurrand-Lions M, Madani R, Yiangou Y, Coffey P, Salt TE, Ducrest-Gay D, Caille D, Howell O, Reynolds R, Lobrinus A, Adams RH, Yu AS, Anand P, Imhof BA and Nourshargh S

    National Heart and Lung Institute, Imperial College London, London, UK.

    JAM-C is an adhesion molecule that is expressed on cells within the vascular compartment and epithelial cells and, to date, has been largely studied in the context of inflammatory events. Using immunolabeling procedures in conjunction with confocal and electron microscopy, we show here that JAM-C is also expressed in peripheral nerves and that this expression is localized to Schwann cells at junctions between adjoining myelin end loops. Sciatic nerves from JAM-C-deficient [having the JAM-C gene knocked out (KO)] mice exhibited loss of integrity of the myelin sheath and defective nerve conduction as indicated by morphological and electrophysiological studies, respectively. In addition, behavioral tests showed motor abnormalities in the KO animals. JAM-C was also expressed in human sural nerves with an expression profile similar to that seen in mice. These results demonstrate that JAM-C is a component of the autotypic junctional attachments of Schwann cells and plays an important role in maintaining the integrity and function of myelinated peripheral nerves.

    Funded by: British Heart Foundation: PG/03/123/16102; NIDDK NIH HHS: R01 DK062283; Wellcome Trust: 064920

    Science (New York, N.Y.) 2007;318;5855;1472-5

  • A role for Nr-CAM in the patterning of binocular visual pathways.

    Williams SE, Grumet M, Colman DR, Henkemeyer M, Mason CA and Sakurai T

    Center for Neurobiology and Behavior and Department of Pathology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.

    Retinal ganglion cell (RGC) axons diverge within the optic chiasm to project to opposite sides of the brain. In mouse, contralateral RGCs are distributed throughout the retina, whereas ipsilateral RGCs are restricted to the ventrotemporal crescent (VTC). While repulsive guidance mechanisms play a major role in the formation of the ipsilateral projection, little is known about the contribution of growth-promoting interactions to the formation of binocular visual projections. Here, we show that the cell adhesion molecule Nr-CAM is expressed by RGCs that project contralaterally and is critical for the guidance of late-born RGCs within the VTC. Blocking Nr-CAM function causes an increase in the size of the ipsilateral projection and reduces neurite outgrowth on chiasm cells in an age- and region-specific manner. Finally, we demonstrate that EphB1/ephrin-B2-mediated repulsion and Nr-CAM-mediated attraction comprise distinct molecular programs that each contributes to the proper formation of binocular visual pathways.

    Funded by: CSR NIH HHS: RG3217-A-8; NEI NIH HHS: EY012736, R01 EY012736, R01 EY015290, T32 EY013933; NINDS NIH HHS: NS040560

    Neuron 2006;50;4;535-47

  • Neurofascins are required to establish axonal domains for saltatory conduction.

    Sherman DL, Tait S, Melrose S, Johnson R, Zonta B, Court FA, Macklin WB, Meek S, Smith AJ, Cottrell DF and Brophy PJ

    Centre for Neuroscience Research, University of Edinburgh, Edinburgh EH9 1QH, United Kingdom.

    Voltage-gated sodium channels are concentrated in myelinated nerves at the nodes of Ranvier flanked by paranodal axoglial junctions. Establishment of these essential nodal and paranodal domains is determined by myelin-forming glia, but the mechanisms are not clear. Here, we show that two isoforms of Neurofascin, Nfasc155 in glia and Nfasc186 in neurons, are required for the assembly of these specialized domains. In Neurofascin-null mice, neither paranodal adhesion junctions nor nodal complexes are formed. Transgenic expression of Nfasc155 in the myelinating glia of Nfasc-/- nerves rescues the axoglial adhesion complex by recruiting the axonal proteins Caspr and Contactin to the paranodes. However, in the absence of Nfasc186, sodium channels remain diffusely distributed along the axon. Our study shows that the two major Neurofascins play essential roles in assembling the nodal and paranodal domains of myelinated axons; therefore, they are essential for the transition to saltatory conduction in developing vertebrate nerves.

    Funded by: Medical Research Council: G0000221, G0301172; Multiple Sclerosis Society: 669; NINDS NIH HHS: R01 NS025304; Wellcome Trust

    Neuron 2005;48;5;737-42

  • Proteomic analysis of in vivo phosphorylated synaptic proteins.

    Collins MO, Yu L, Coba MP, Husi H, Campuzano I, Blackstock WP, Choudhary JS and Grant SG

    Division of Neuroscience, University of Edinburgh, Edinburgh EH8 9JZ, UK.

    In the nervous system, protein phosphorylation is an essential feature of synaptic function. Although protein phosphorylation is known to be important for many synaptic processes and in disease, little is known about global phosphorylation of synaptic proteins. Heterogeneity and low abundance make protein phosphorylation analysis difficult, particularly for mammalian tissue samples. Using a new approach, combining both protein and peptide immobilized metal affinity chromatography and mass spectrometry data acquisition strategies, we have produced the first large scale map of the mouse synapse phosphoproteome. We report over 650 phosphorylation events corresponding to 331 sites (289 have been unambiguously assigned), 92% of which are novel. These represent 79 proteins, half of which are novel phosphoproteins, and include several highly phosphorylated proteins such as MAP1B (33 sites) and Bassoon (30 sites). An additional 149 candidate phosphoproteins were identified by profiling the composition of the protein immobilized metal affinity chromatography enrichment. All major synaptic protein classes were observed, including components of important pre- and postsynaptic complexes as well as low abundance signaling proteins. Bioinformatic and in vitro phosphorylation assays of peptide arrays suggest that a small number of kinases phosphorylate many proteins and that each substrate is phosphorylated by many kinases. These data substantially increase existing knowledge of synapse protein phosphorylation and support a model where the synapse phosphoproteome is functionally organized into a highly interconnected signaling network.

    The Journal of biological chemistry 2005;280;7;5972-82

  • CNS myelin paranodes require Nkx6-2 homeoprotein transcriptional activity for normal structure.

    Southwood C, He C, Garbern J, Kamholz J, Arroyo E and Gow A

    Brookdale Center for Molecular Biology, Mount Sinai School of Medicine, New York, New York, 10029, USA.

    Homeodomain proteins play critical roles during development in cell fate determination and proliferation, but few studies have defined gene regulatory networks for this class of transcription factors in differentiated cells. Using a lacZ-knock-in strategy to ablate Nkx6-2, we find that the Nkx6-2 promoter is active embryonically in neuroblasts and postnatally in oligodendrocytes. In addition to neurological deficits, we find widespread ultrastructural abnormalities in CNS white matter and aberrant expression of three genes encoding a paranodal microtubule destabilizing protein, stathmin 1, and the paranodal cell adhesion molecules neurofascin and contactin. The involvement of these downstream proteins in cytoskeletal function and cell adhesion reveals mechanisms whereby Nkx6-2 directly or indirectly regulates axon- glial interactions at myelin paranodes. Nkx6-2 does not appear to be the central regulator of axoglial junction assembly; nonetheless, our data constitute the first evidence of such a regulatory network and provide novel insights into the mechanism and effector molecules that are involved.

    Funded by: NIDCD NIH HHS: DC006262, R01 DC006262

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2004;24;50;11215-25

  • Ankyrin-based subcellular gradient of neurofascin, an immunoglobulin family protein, directs GABAergic innervation at purkinje axon initial segment.

    Ango F, di Cristo G, Higashiyama H, Bennett V, Wu P and Huang ZJ

    Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.

    Distinct classes of GABAergic synapses are segregated into subcellular domains (i.e., dendrite, soma, and axon initial segment-AIS), thereby differentially regulating the input, integration, and output of principal neurons. In cerebellum, for example, basket interneurons make exquisitely precise "pinceau synapses" on AIS of Purkinje neurons, but the underlying mechanism is unknown. Using BAC transgenic reporter mice, we found that basket axons always contacted Purkinje soma before innervating AIS. This synapse targeting process followed the establishment of a subcellular gradient of neurofascin186 (NF186), an L1 family immunoglobulin cell adhesion molecule (L1CAM), along the Purkinje AIS-soma axis. This gradient was dependent on ankyrinG, an AIS-restricted membrane adaptor protein that recruits NF186. In the absence of neurofascin gradient, basket axons lost directional growth along Purkinje neurons and precisely followed NF186 to ectopic locations. Disruption of NF186-ankyrinG interactions at AIS reduced pinceau synapse formation. These results implicate ankyrin-based localization of L1CAMs in subcellular organization of GABAergic synapses.

    Cell 2004;119;2;257-72

  • Wnk1 kinase deficiency lowers blood pressure in mice: a gene-trap screen to identify potential targets for therapeutic intervention.

    Zambrowicz BP, Abuin A, Ramirez-Solis R, Richter LJ, Piggott J, BeltrandelRio H, Buxton EC, Edwards J, Finch RA, Friddle CJ, Gupta A, Hansen G, Hu Y, Huang W, Jaing C, Key BW, Kipp P, Kohlhauff B, Ma ZQ, Markesich D, Payne R, Potter DG, Qian N, Shaw J, Schrick J, Shi ZZ, Sparks MJ, Van Sligtenhorst I, Vogel P, Walke W, Xu N, Zhu Q, Person C and Sands AT

    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381, USA. brian@lexgen.com

    The availability of both the mouse and human genome sequences allows for the systematic discovery of human gene function through the use of the mouse as a model system. To accelerate the genetic determination of gene function, we have developed a sequence-tagged gene-trap library of >270,000 mouse embryonic stem cell clones representing mutations in approximately 60% of mammalian genes. Through the generation and phenotypic analysis of knockout mice from this resource, we are undertaking a functional screen to identify genes regulating physiological parameters such as blood pressure. As part of this screen, mice deficient for the Wnk1 kinase gene were generated and analyzed. Genetic studies in humans have shown that large intronic deletions in WNK1 lead to its overexpression and are responsible for pseudohypoaldosteronism type II, an autosomal dominant disorder characterized by hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Consistent with the human genetic studies, Wnk1 heterozygous mice displayed a significant decrease in blood pressure. Mice homozygous for the Wnk1 mutation died during embryonic development before day 13 of gestation. These results demonstrate that Wnk1 is a regulator of blood pressure critical for development and illustrate the utility of a functional screen driven by a sequence-based mutagenesis approach.

    Proceedings of the National Academy of Sciences of the United States of America 2003;100;24;14109-14

  • Association of TAG-1 with Caspr2 is essential for the molecular organization of juxtaparanodal regions of myelinated fibers.

    Traka M, Goutebroze L, Denisenko N, Bessa M, Nifli A, Havaki S, Iwakura Y, Fukamauchi F, Watanabe K, Soliven B, Girault JA and Karagogeos D

    Department of Basic Science, University of Crete Medical School, Heraklion 71110, Crete, Greece.

    Myelination results in a highly segregated distribution of axonal membrane proteins at nodes of Ranvier. Here, we show the role in this process of TAG-1, a glycosyl-phosphatidyl-inositol-anchored cell adhesion molecule. In the absence of TAG-1, axonal Caspr2 did not accumulate at juxtaparanodes, and the normal enrichment of shaker-type K+ channels in these regions was severely disrupted, in the central and peripheral nervous systems. In contrast, the localization of protein 4.1B, an axoplasmic partner of Caspr2, was only moderately altered. TAG-1, which is expressed in both neurons and glia, was able to associate in cis with Caspr2 and in trans with itself. Thus, a tripartite intercellular protein complex, comprised of these two proteins, appears critical for axo-glial contacts at juxtaparanodes. This complex is analogous to that described previously at paranodes, suggesting that similar molecules are crucial for different types of axo-glial interactions.

    Funded by: NINDS NIH HHS: R01 NS039346, R01 NS39346-01

    The Journal of cell biology 2003;162;6;1161-72

  • Prediction of the coding sequences of mouse homologues of KIAA gene: III. the complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs identified by screening of terminal sequences of cDNA clones randomly sampled from size-fractionated libraries.

    Okazaki N, Kikuno R, Ohara R, Inamoto S, Koseki H, Hiraoka S, Saga Y, Nagase T, Ohara O and Koga H

    Kazusa DNA Research Institute, 2-6-7 Kazusa-kamatari, Kisarazu, Chiba 292-0818, Japan.

    We have conducted a human cDNA project to predict protein-coding sequences (CDSs) in large cDNAs (> 4 kb) since 1994, and the number of newly identified genes, known as KIAA genes, already exceeds 2000. The ultimate goal of this project is to clarify the physiological functions of the proteins encoded by KIAA genes. To this end, the project has recently been expanded to include isolation and characterization of mouse KIAA-counterpart genes. We herein present the entire sequences and the chromosome loci of 500 mKIAA cDNA clones and 13 novel cDNA clones that were incidentally identified during this project. The average size of the 513 cDNA sequences reached 4.3 kb and that of the deduced amino acid sequences from these cDNAs was 816 amino acid residues. By comparison of the predicted CDSs between mouse and human KIAAs, 12 mKIAA cDNA clones were assumed to be differently spliced isoforms of the human cDNA clones. The comparison of mouse and human sequences also revealed that four pairs of human KIAA cDNAs are derived from single genes. Notably, a homology search against the public database indicated that 4 out of 13 novel cDNA clones were homologous to the disease-related genes.

    DNA research : an international journal for rapid publication of reports on genes and genomes 2003;10;4;167-80

  • Neurofascin is a glial receptor for the paranodin/Caspr-contactin axonal complex at the axoglial junction.

    Charles P, Tait S, Faivre-Sarrailh C, Barbin G, Gunn-Moore F, Denisenko-Nehrbass N, Guennoc AM, Girault JA, Brophy PJ and Lubetzki C

    INSERM U-495, Biologie des Interactions Neurones/Glie, UPMC, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France.

    In myelinated fibers of the vertebrate nervous system, glial-ensheathing cells interact with axons at specialized adhesive junctions, the paranodal septate-like junctions. The axonal proteins paranodin/Caspr and contactin form a cis complex in the axolemma at the axoglial adhesion zone, and both are required to stabilize the junction. There has been intense speculation that an oligodendroglial isoform of the cell adhesion molecule neurofascin, NF155, expressed at the paranodal loop might be the glial receptor for the paranodin/Caspr-contactin complex, particularly since paranodin/Caspr and NF155 colocalize to ectopic sites in the CNS of the dysmyelinated mouse Shiverer mutant. We report that the extracellular domain of NF155 binds specifically to transfected cells expressing the paranodin/Caspr-contactin complex at the cell surface. This region of NF155 also binds the paranodin/Caspr-contactin complex from brain lysates in vitro. In support of the functional significance of this interaction, NF155 antibodies and the extracellular domain of NF155 inhibit myelination in myelinating cocultures, presumably by blocking the adhesive relationship between the axon and glial cell. These results demonstrate that the paranodin/Caspr-contactin complex interacts biochemically with NF155 and that this interaction is likely to be biologically relevant at the axoglial junction.

    Funded by: Medical Research Council: G0000221

    Current biology : CB 2002;12;3;217-20

  • Structural and functional evolution of the L1 family: are four adhesion molecules better than one?

    Hortsch M

    Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, 48109-0616, USA.

    Funded by: NICHD NIH HHS: HD29388

    Molecular and cellular neurosciences 2000;15;1;1-10

  • Cloning of 5'-flanking region and a polymorphic CTT trinucleotide repeat within 5'-untranslated region of mouse R-type calcium channel alpha1-subunit (Cchra1) gene, and its genetic mapping.

    Yamazaki K, Oki T and Tanaka I

    Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3, Tokodai, Tsukuba, Ibaraki 300-2635, Japan.

    The 5'-flanking region of the mouse R-type calcium channel (Cchra1) gene was cloned, and a transcriptional start point (tsp) was determined by rapid amplification of 5'-cDNA end (5'RACE) method. The putative promoter region of the gene contained no obvious TATA or CCAAT element in the expected positions, but multiple putative binding sites for transcriptional factors, such as Sp1, AP-1, AP-2, AP-3, EGR-1, EGR-2, NF-kappaB and HIP1, were detected. We found the existence of a tandem CTT trinucleotide repeat within the 5'-untranslated region (UTR) of the gene, and its polymorphism between C57BL/6J and Mus spretus. Using this polymorphism, the Cchra1 was mapped to the region of chromosome 1 where the synteny to human chromosome 1q was conserved.

    Gene 1998;214;1-2;199-204

  • Genes for the neuronal immunoglobulin domain cell adhesion molecules neurofascin and Nr-CAM map to mouse chromosomes 1 and 12 and homologous human chromosomes.

    Burmeister M, Ren Q, Makris GJ, Samson D and Bennett V

    Mental Health Research Institute, 205 Zina Pitcher Place, University of Michigan, Ann Arbor, 48109-0720, USA.

    Funded by: NINDS NIH HHS: NS32130

    Mammalian genome : official journal of the International Mammalian Genome Society 1996;7;7;558-9

  • Cloning and expression of a murine fascin homolog from mouse brain.

    Edwards RA, Herrera-Sosa H, Otto J and Bryan J

    Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030, USA.

    The fascins are a widely distributed family of proteins that organize filamentous actin into bundles. We have cloned, sequenced, and expressed the murine homolog. Fascin is most abundant in brain and is found in other tissues including uterus and spleen. The deduced open reading frame encodes a protein of 493 amino acids with a molecular mass of 54,412 Da. Previous solubility problems with bacterially expressed fascins were overcome by producing the mouse protein as a fusion with Escherichia coli thioredoxin. A method for cleaving the fusion protein and for purifying active recombinant fascin is described. The N-terminal sequence and molecular mass estimated on SDS gels indicate that recombinant fascin is full-length. Two-dimensional gel electrophoresis suggests that recombinant fascin is post-translationally modified in a manner similar to that observed in mouse brain. Recombinant fascin and the fusion protein are recognized by monoclonal anti-fascin antibodies and will bundle rabbit skeletal muscle F-actin in vitro at a stoichiometry of 4.1:1 actin to fascin. Electron cryomicroscopy images show that the reconstituted bundles are highly ordered. However, their fine structure differs from that of echinoid fascin-actin bundles. This structural difference can be attributed to fascin.

    The Journal of biological chemistry 1995;270;18;10764-70

  • Expression of four immunoglobulin superfamily adhesion molecules (L1, Nr-CAM/Bravo, neurofascin/ABGP, and N-CAM) in the developing mouse spinal cord.

    Moscoso LM and Sanes JR

    Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

    To identify cell adhesion molecules (CAMs) expressed by mammalian motoneurons, we applied the polymerase chain reaction to a murine motor neuron-like cell line, NSC-34. Using primers derived from a group of L1-related CAMs, we cloned two alternatively spliced forms of mouse L1, which differ by a 12-base-pair insert, plus putative murine orthologs of the chicken cell adhesion molecules Nr-CAM/Bravo and neurofascin. All four mRNAs are expressed in NSC-34 cells, but only neurofascin and the insert-minus form of L1 are expressed in its neuroblastoma parent, N18TG2. Analysis of RNA in neonatal tissues reveals expression largely restricted to the brain and spinal cord. In situ hybridization histochemistry of spinal cord shows that motoneurons express L1, Nr-CAM, and neurofascin as well as N-CAM. L1 and N-CAM RNAs are detected throughout the period studied (from embryonic day [E]11 to postnatal day [P]28), whereas Nr-CAM is expressed only at early ages (< E15) and neurofascin is predominantly expressed postnatally. Moreover, each CAM is expressed by distinct subsets of neighboring cells and at distinct times. For example, Nr-CAM mRNA is present in floor plate cells of embryonic spinal cord, whereas neurofascin is expressed by a subset of glia postnatally. Finally, we show that each CAM has a distinct spatiotemporal pattern of expression in dorsal root ganglia.

    The Journal of comparative neurology 1995;352;3;321-34

Gene lists (6)

Gene List Source Species Name Description Gene count
L00000001 G2C Mus musculus Mouse PSD Mouse PSD adapted from Collins et al (2006) 1080
L00000008 G2C Mus musculus Mouse PSP Mouse PSP adapted from Collins et al (2006) 1121
L00000060 G2C Mus musculus BAYES-COLLINS-HUMAN-PSD-CONSENSUS Human cortex PSD consensus (ortho) 748
L00000062 G2C Mus musculus BAYES-COLLINS-MOUSE-PSD-CONSENSUS Mouse cortex PSD consensus 984
L00000070 G2C Mus musculus BAYES-COLLINS-HUMAN-PSD-FULL Human cortex biopsy PSD full list (ortho) 1461
L00000072 G2C Mus musculus BAYES-COLLINS-MOUSE-PSD-FULL Mouse cortex PSD full list 1556
© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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