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FLASH GENE
Symbol RTN4 contributors: mct/npt/pg/shn - updated : 16-06-2013
HGNC name reticulon 4
HGNC id 14085
Location 2p16.1      Physical location : 55.199.328 - 55.277.734
Synonym name
  • foocen
  • neurite growth inhibitor 220
  • neurite outgrowth inhibitor
  • neuroendocrine-specific protein C homolog
  • reticulon 5
  • reticulon-4
  • Synonym symbol(s) NOGO-B, NOGO-C, NSP-CL, NOGO, KIAA0886, ASY, NOGO-A, NSP, RTN-X, RTN4-A, RTN4-C, RTN4-B1, RTN4-B2, NI220/250, Nbla00271, Nbla10545, Foocen, My043, ASY, SP-CL
    DNA
    TYPE functioning gene
    STRUCTURE 78.41 kb     9 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter (CAAT box)
    cytosine-phosphate-guanine/HTF
    Binding site   silencer
    text structure
  • conserved GC-boxes and a CCAAT-box within the first 500bp upstream of the transcription start are responsible for regulation of NOGO-A/B promoter (P1)
  • basal Nogo-C promoter (P2) is regulated by a proximal and a distal element.
  • MAPPING cloned Y linked N status provisional
    Map pter - D2S2251 - D2S2153 - RTN4 - D2S378 - D2S2279 - cen
    Physical map
    CRYGGP1 2q33-q35 crystallin, gamma G pseudogene 1 LOC129656 2p16.3 similar to MECT1 protein LOC388949 2 similar to signal-transducing adaptor protein-2; brk kinase substrate ASB3 2p16-p14 ankyrin repeat and SOCS box-containing 3 XTP3TPB 2p16.3 XTP3-transactivated protein B GPR75 2p16 G protein-coupled receptor 75 PSME4 2p16.1 proteasome (prosome, macropain) activator subunit 4 LOC388950 2 similar to hypothetical protein ACYP2 2p16.2 acylphosphatase 2, muscle type LOC388951 2 similar to Testis-specific Y-encoded-like protein 1 (TSPY-like 1) FLJ40298 2p16.3 hypothetical protein FLJ40298 SPTBN1 2p16 spectrin, beta, non-erythrocytic 1 DKFZp547I014 2p16.3 hypothetical protein DKFZp547I014 RTN4 2p14-p13 reticulon 4 FLJ31438 2p16.3 hypothetical protein FLJ31438 RPS27A 2p16 ribosomal protein S27a MTIF2 2p16-p14 mitochondrial translational initiation factor 2 LOC344405 2p16.3 similar to RIKEN cDNA 2010316F05 LOC55580 2p16.3 hypothetical protein LOC55580 MGC15407 2p16.2 similar to RIKEN cDNA 4931428D14 gene KIAA1387 2p16.2 KIAA1387 protein PNPT1 2p15 polyribonucleotide nucleotidyltransferase 1 EFEMP1 2p16 EGF-containing fibulin-like extracellular matrix protein 1 LOC388952 2 LOC388952 KIAA1912 2p16.2 KIAA1912 protein LOC391374 2 similar to Eukaryotic translation initiation factor 2 subunit 2 (Eukaryotic translation initiation factor 2 beta subunit) (eIF-2-beta) LOC391375 2 similar to actin VRK2 2p16-p15 vaccinia related kinase 2 FANCL 2p16.1 Fanconi anemia, complementation group L LOC339799 2p16.1 similar to eukaryotic translation initiation factor 3, subunit 5 epsilon, 47kDa; eukaryotic translation initiation factor 3, subunit 5 (epsilon, 47kD); eIF3-epsilon LOC151443 2p16.1 hypothetical LOC151443 LOC151445 2p16.1 similar to IK cytokine; arginine/glutamic acid/aspartic acid repeat containing protein
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    9 splicing 4871 130 1192 expressed in various neuronal cell types including differentiated neurones and predominantly expressed by oligodendrocytes 2000 11126360
  • also called NOGO-A, RTN-XL, variant 1-isoform A
  • membrane protein impairing neurite growth
  • mediating with MAG neurite growth inhibition by antagonistic regulation of ARHA and RAC1
  • overexpressed in amyotrophic lateral sclerosis (ALS)
  • a 180 AA C-terminal domain with two highly conserved hydrophobic stretches that could form a channel or transporter in the ER and/or on the cell surface
  • N-terminal domain of Nogo-A inhibits cell adhesion and axonal outgrowth by an integrin-specific mechanism
  • 7 splicing 2414 40.3 373 widely except liver, highly in endothelial and smooth muscle cells of the vessel wall 2009 19805174
  • also called NOGO-B, foocen M, RTN-XS, RTN4-B1, variant 2-isoform B
  • acting as a regulator of vascular homeostasis
  • lacking an in-frame segment of the coding region compared to NOGO-A
  • a 180 AA C-terminal domain with two highly conserved hydrophobic stretches that could form a channel or transporter in the ER and/or on the cell surface
  • physiological substrate of MAPKAPK2
  • important Nogo-B function during inflammation
  • 4 splicing 1808 22.3 199 brain, adipocyte, highly skeletal muscle 2000 11126360
  • also called NOGO-C, foocen S, variant 3
  • differing in the 5' UTR and the 5' coding region compared to NOGO-A
  • a 180 AA C-terminal domain with two highly conserved hydrophobic stretches that could form a channel or transporter in the ER and/or on the cell surface
  • 8 splicing 2471 42 392 - 2000 11126360
  • also called Foocen-m2, RTN4-B2 , variant 4-isoform D
  • lacking an in-frame segment of the coding region compared to NOGO-A
  • 9 splicing 4129 108 986 - 2000 11126360
  • also called hRTN4-E, variant 5-isoform E
  • differing in the 5' UTR and the 5' coding region compared to NOGO-A
  • EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularvessel   highly Homo sapiens
    Hearing/Equilibriumearinnercochlea moderately Homo sapiens
    Nervousbrain     Homo sapiensAdult
     nervecranial nerveoptic nerve  
    Reproductivemale systemtestis   
    Urinarybladder   highly
     kidney   moderately
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectivebone   
    Muscularsmoothvessel   Homo sapiens
    Nervouscentralwhite matter   Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticmonocyte Homo sapiens
    Cardiovascularendothelial cell Homo sapiens
    Lymphoid/Immunemacrophage Homo sapiens
    Nervousglia Homo sapiensAdult
    Nervousneuron Homo sapiensAdult
    Nervousoligodendrocyte Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period embryo
    Text
  • muscle
  • during development, also expressed by neurons
  • PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N terminal luminal/extracellular negatively charged domain
  • two hydrophobic transmembrane segments (TM2)
  • a conserved C terminal region
  • a reticulon domain
  • two major inhibitory regions, first is a stretch in the middle (AA 567-748), restricting neurite outgrowth and cell spreading and induces growth cone collapse
  • second is the extracellular 66 AAs loop, Nogo-66 capable of inhibiting neurite growth and inducing growth cone collapse, with N-terminal 40 AA named Nogo-40
  • A 172-AAs N-terminal region and a 37-AAs C-terminal region both could inhibit neuronal differentiation and promoted glial cell formation
  • HOMOLOGY
    interspecies ortholog to Rtn4, Rattus norvegicus
    ortholog to Rtn4, Mus musculus
    ortholog to RTN4, Pan troglodytes
    intraspecies homolog to RTN1, RTN2 and RTN3
    Homologene
    FAMILY reticulon family
    CATEGORY signaling growth factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,cytoskeleton
    intracellular,nuclear envelope,ext
    text
  • anchored to membranes of the endoplasmic reticulum through its carboxy-terminal regions
  • synaptic localization of Nogo-A (
  • association with cytoskeletal structures and the base of filopodia, but not with focal or podosomal adhesion sites of monocyte-derived macrophages, also associated with the tubulin network, but not accumulated in the Golgi region
  • basic FUNCTION
  • neurite outgrow inhibitor, limiting axonal regeneration after nervous injury
  • role central in sporadic and familial amyotrophic lateral sclerosis
  • multidomain protein containing several discrete regions with growth inhibitory functions
  • regulating, in association with RTN4R, CNS axonal plasticity and recovery from injury
  • can modulate the anti-apoptotic activity of BCL2L1 and BCL2 by binding with them and can change their localization to the ER
  • participate in the neuronal responses stemming from hippocampal formation during senescence, and particularly in Alzheimer disease
  • RTN4 and MAG are differently involved in oligodendrocyte maturation , suggesting that RTN4 may influence also remyelination in pathological conditions such as multiple sclerosis
  • N terminus of Nogo-B promotes the migration of endothelial cells but inhibits the migration of vascular smooth muscle cells (
  • Nogo-B is a regulator of vascular homeostasis (
  • Nogo A is involved in central nervous system autoimmune demyelination (
  • role of Nogo-A for myelin formation in the developing optic nerve (
  • endogenous regulator of inflammatory tissue remodeling and wound healing that is mediated, in part, via impaired macrophage homing to ischemic tissue and wounds
  • role in neuronal migration (
  • neuronal form plays an important role in regulating cytoskeletal re-organization without the requirement of signaling through its cognate receptor (RTN4R)
  • developmental neurite growth regulatory factor with a role as a negative regulator of axon-axon adhesion and growth, and as a facilitator of neurite branching
  • plays a major role in stabilizing and maintaining the architecture of hippocampal pyramidal neurons
  • functioning as a negative regulator of neuronal growth, leading to stabilization of the CNS wiring at the expense of extensive plastic rearrangements and regeneration after injury
  • may have roles in the regulation of endoplasmic reticulum (ER) structure, processing of amyloid precursor protein and cell survival
  • physiological roles of RTN4, MAG, OMG in processes, such as development, neuronal homeostasis, plasticity, and neurodegeneration
  • endothelial RTN4 regulates leukocyte transmigration and intercellular adhesion molecule-1 (ICAM1)-dependent signaling, and acute inflammation
  • could play a role in the regulation of Purkinje cells (PCs) connectivity
  • distinct biological function for RTN4 expressed by neurons for the development of synaptic connections in the cerebellum
  • CELLULAR PROCESS cell life, antiapoptosis
    cell organization/biogenesis
    PHYSIOLOGICAL PROCESS
    text
  • important regulators of cell motility and growth
  • not altering the morphology of non neuronal cells
  • negative regulation of anti-apoptosis
  • negative regulation of axon extension
  • PATHWAY
    metabolism
    signaling
    Nogo signaling has critical roles in development and maintenance of the central nervous system (CNS)
    a component
  • complex with RTN4R (play a modulated role in limiting CNS axonal growth across a spectrum of different tracts in various lesions)
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • Bcl-2 and Bcl-XL (
  • Nogo receptor 1, NgR1 (
  • UQCRC1, UQCRC2 and Nogo-interacting mitochondrial protein, NIMP (
  • alpha-tubulin and myelin basic protein, MBP (
  • ASY interacting protein, ASYIP (
  • Caspr-F3 complex at paranodes (
  • Nogo-B specific receptor, NGBR (
  • immunoglobulin-like receptor B, PIRB (
  • WW domain containing E3 ubiquitin protein ligase 1, WWP1 (
  • interactions of RTN4R with its co-receptors LINGO1, NGFR and the myelin inhibitor RTN4 is facilitated by gangliosides
  • S1PR2 is a receptor for RTN4 repressing synaptic plasticity
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in amyotrophic lateral sclerosis (ALS)
    constitutional     --over  
    by hippocampal neurons in AD and is associated with beta-amyloid deposits in senile plaques
    Susceptibility to dilated cardiomyopathy (DCM)
    Variant & Polymorphism other RTN4 allele (TATC)(2) and (TATC)(2)/(TATC)(2) genotype are associated with DCM
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurologyacquired 
    Silencing Nogo-A may be a therapeutic option for multiple sclerosis patients to prevent permanent functional deficits caused by immune-mediated axonal damage
    ANIMAL & CELL MODELS
  • Nogo-A-deficient mice are viable, fertile, and not afflicted by major developmental or neurological disturbances and display more corticospinal tract (CST) fibers growing toward and into the lesion (
  • Nogo-A/B-deficient myelin has reduced inhibitory activity of axon regeneration in a neurite outgrowth assay in vitro (
  • vascular injury in Nogo-A/B-deficient mice promotes exaggerated neointimal proliferation, and adenoviral-mediated gene transfer of Nogo-B rescues the abnormal vascular expansion in those animals (
  • mice vaccinated against Nogo A produce Nogo-specific antibodies that block the neurite outgrowth inhibitory activity associated with CNS myelin in vitro (
  • overexpression of Nogo-A leads to an increase in the proportion of tubular endoplasmic reticulum but prevents the assembly of the nuclear membrane after cell division (
  • overexpression of Nogo-A in mouse Purkinje terminals induced synapse disassembly (
  • optic nerves and cerebella of mice deficient for Nogo-A (Nogo-A(-/-)) revealed a marked delay of oligodendrocyte differentiation, myelin sheath formation, and axonal caliber growth within the first postnatal month
  • Nogo-A deletion in mice reduces muscle denervation and prolongs survival, whereas overexpression of Nogo-A destabilizes motor nerve terminals and promotes denervation
  • depletion of a Nogo isoform causes truncated outgrowth of peripheral nervous system axons of the head and lateral line in zebrafish (
  • adult mice lacking Nogo-A showed an upregulation of cytoskeletal and growth-related mRNAs, and proteins in the spinal cord and cortex (
  • in a superoxide dismutase mutant mouse model of amyotrophic lateral sclerosis, genetic deletion of Nogo-A and Nogo-B accelerate disease progression and decrease spinal motor neuron survival (
  • Nogo-A knockout mice display schizophrenia-like behavioural phenotype (
  • increased fibre sprouting occurs around amyloid plaques in Nogo knockout mice (