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FLASH GENE
Symbol RELN contributors: mct - updated : 03-07-2017
HGNC name reelin
HGNC id 9957
Corresponding disease
ETL7 epilepsy, familial temporal lobe, 7
LIS2 lissencephaly 2
Location 7q22.1      Physical location : 103.112.232 - 103.629.963
Synonym symbol(s) RLR, RL, PRO1598, LIS2, ETL7
EC.number 3.4.21.-
DNA
TYPE functioning gene
STRUCTURE 517.73 kb     64 Exon(s)
10 Kb 5' upstream gene genomic sequence study
regulatory sequence Promoter
cytosine-phosphate-guanine/HTF
Binding site   HRE
text structure
  • a CGG repeat in 5'utr
  • CpG islands flanking a CRE and Sp1 binding site
    • MAPPING cloned Y linked N status confirmed
    Map cen - D7S1503 - D7S2509- RELN - D7S658 - D7S2446 - qter
    Authors Kratz (01)
    regionally located in a segment commonly deleted in myeloid malignancy
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    65 splicing 11571 420 3460 - 1999 10571240
    64 splicing 11565 388 3458 - 1999 10571240
    lacking an in-frame, 6 nt microexon in the coding region compared to variant 1, resulting in an isoform b that is 2 aa shorter than isoform a
    - - - 160 - - -
  • in the serum, only trace amounts of the 160-kDa isoform are present
    • - - - 310 - - -
  • in the serum, the 310-kDa isoform accounts for most of the signal (>80p100)
    		•
    EXPRESSION
    Type
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Hearing/Equilibriumearinnercochlea highly
    Nervousbrainforebraincerebral cortex   Homo sapiensFetal
     brain   predominantly Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Nervouscentral    Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousneuron Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal, perinatal, pregnancy
    Text brain, liver, cerebellum
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • . N-terminal signal peptide
  • 15 BNR repeats
  • 8 EGF-like domains
  • eight tandem repeats of 350–390 residues termed “Reelin repeats”
  • an F-spondin-like domain, a unique region
    • conjugated GlycoP
    HOMOLOGY
    interspecies ortholog to Reln, Mus musculus
    ortholog to Reln, Rattus norvegicus
    ortholog to RELN, Pan troglodytes
    ortholog to reln, danio rerio
    Homologene
    FAMILY
  • reelin family
    • CATEGORY adhesion , secretory , signaling
    SUBCELLULAR LOCALIZATION extracellular
        intracellular
    intracellular,cytoplasm
    text
  • secreted by Cajal-Retzius cells, extracellular matrix protein
  • specifically localized in enteric neurons with highest expression levels during early postnatal life
    • basic FUNCTION
  • molecular barrier to neuronal migration by binding to VLDLR and LRP8
  • directs neuronal migration by binding to VLDLR and LRP8
  • modulating the structure and function of retinal synaptic circuitry and of the central nervous system and synaptic plasticity
  • RELN and GRM8 genes are likely involved in the pathogenesis of autistic disorder
  • implicated in the pathogenesis of otosclerosis
  • with NOTCH1 is necessary to induce the expression of brain lipid binding protein (FABP7) and to promote the process extension and the maturation of the neuronal progenitors, the radial glial cells
  • extracellular matrix protein synthesized in cerebellar granule cells that plays an important role in Purkinje cell positioning during cerebellar development and in modulating adult synaptic function
  • RELN and STK25 have opposing roles in neuronal polarization and dendritic Golgi deployment
  • essential for the targeting of lateral geniculate nucleus subnuclei by functionally distinct classes of retinal ganglion cells
  • important for multipolar neurons to polarize their migration toward the cortical plate
  • regulates neurons migration through Rap1 and Akt
  • likely promotes microtubule assembly, at least in part, by increasing microtubule plus end dynamics
  • RELN and the CDC42/RAC1 guanine nucleotide exchange factor ARHGEF6 promote dendritic Golgi translocation in hippocampal neurons
  • critical for proper layering of neocortex during development as well as dynamic regulation of glutamatergic postsynaptic signaling in mature synapses
  • regulates the somatosensory barrel cortex differently than other neocortical areas
  • DAB1 functions downstream of reelin action on the homeostasis of the crypt-villus unit
  • coordinates migration and lamination of neurons and regulates synaptic plasticity
  • large secreted glycoprotein that plays essential roles in the cytoarchitecture of laminated brain structures and modulation of synaptic transmission and plasticity
  • important functions in both the developing and adult brain and is also found in the blood serum
  • extracellular glycoprotein that is secreted by Cajal-Retzius cells during embryogenesis and by GABAergic neurons in the post-natal brain
  • extracellular glycoprotein that is essential for migration and correct positioning of neurons during development
  • possible involvements of RELN and DAB1 in the peripheral migrating stream
  • is a large extracellular matrix glycoprotein and governs cell migration through activation of multiple intracellular signaling events by means of the receptors LRP8 and VLDLR, and the intracellular adaptor protein Disabled-1 (DAB1)
  • during neuronal migration RELN interacts with PAFAH1B1 and induces nuclear translocation, accompanied by the ubiquitination of phosphorylated DAB1
  • extracellular Reelin binds to cell surface receptors and activates phosphorylation of the intracellular DAB1 protein
  • secreted glycoprotein Reelin is an important factor directing neuronal migration
    • CELLULAR PROCESS cell organization/biogenesis
    cell communication
    PHYSIOLOGICAL PROCESS
    text neuronal migration in the spinal cord
    PATHWAY
    metabolism
    signaling signal transduction
  • RELN could be involved in the tissue specificity of SCA7
  • important role for RELN-DAB1 signaling in the adult forebrain
  • RELN/DAB1 signaling in the embryonic limb regulates the chondrogenic differentiation of digit mesodermal progenitors
    • a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • EMX2 for the neuronal migration
  • PAFAH1B1 (for brain development)
  • lipoprotein receptors, preferably the very low-density lipoprotein receptor, VLDLR and apolipoprotein E receptor 2, LRP8 (
  • cannabinoid receptor 1 (brain), CNR1 (
  • PAFAH1B1 in brain development (
  • proteolytic cleavage of RELN and alternative splicing of LRP8 may be involved in the fine regulation of RELN signaling
  • TBR1(
  • ephrin B1, B2, B3 (
  • induction of Disabled-1 (DAB1) tyrosine phosphorylation, and the subsequent activation of Src family kinases, were found to be essential steps for the activation of NOTCH1 signaling by RELN
  • ADAMTS4 cleaves RELN in an isoform-specific manner
  • LRP8 is being the main receptor responsible for RELN mediated detachment of neuroblasts and correct migration of early generated interneurons within the olfactory bulb (OB), a prerequisite for correct OB lamination
  • RELN is a target of polyglutamine expanded ATXN7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes
  • RELN binds to the extracellular domains of EPHB1, EPHB2 transmembrane proteins, inducing receptor clustering and activation of EPHB forward signaling in neurons, independently of the 'classical' Reelin receptors, APOER2 and VLDLR
  • ligand of LRP8 or VLDLR
  • SH3KBP1 participates in Reelin signaling through the binding to DAB1
  • major role of VEGFA in the regulation of RELN signaling, and DAB1 as a key molecule in the cross talk between reelin and VEGFA signaling pathways
  • mobilizes a VAMP7-dependent synaptic vesicle pool and selectively augments spontaneous neurotransmission
  • activation of Erk1/2 signaling likely contributes to the modulation of neuronal maturation and synaptic plasticity by RELN in the postnatal and adult brain
  • link between RELN and LGI1, which play key regulatory roles in both the developing and adult brain
  • by terminating RELN signaling, SOCS6 and SOCS7 may allow new cycles of RELN signaling to occur and these may be essential for cortical neuron migration
  • RELN transiently (and not persistently) promotes CDH2-mediated neuronal aggregation
  • ITSN1 is a component of RELN signaling that acts predominantly by facilitating the VLDLR-DAB1 axis to direct neuronal migration in the cortex and hippocampus and to augment synaptic plasticity
    • cell & other
    REGULATION
    Other targeted by CASK
    after bbinding to its receptor, RELN is internalized by endocytosis for proteolysis and the N terminal fragment is re-secreted
    ASSOCIATED DISORDERS
    corresponding disease(s) LIS2 , ETL7
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    in cortical GABAergic neurons of schizophrenic brain (by hypermethylation of the promoter)
    tumoral     --over  
    coordinate overexpression of CASK and RELN in carcinoma of esophagus
    constitutional     --low  
    impairs GABAergic Purkinje neuron expression and/or positioning during cerebellar development
    constitutional     --low  
    in the cerebral cortex and cerebellum of subjects with autism
    Susceptibility
  • susceptibility factor for schizophrenia
  • susceptibility to autism
  • to otosclerosis
  • to Alzheimer disease
  • to Myoclonus-dystonia (M-D)
    • Variant & Polymorphism SNP
  • SNP in intron 59, and 5'-UTR repeat increasing the risk of autism
  • SNPs increasing the risk of otosclerosis
  • rs607755 genotypes increasing the risk of Alzheimer disease in females and not in males
  • rare missense variant Thr1904Met associated with Myoclonus-dystonia (M-D)
    • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • Reln homozygous mutations in mouse result ataxia and disrupted cortical layers (
  • Loss of Reelin function in humans results in the severe developmental disorder lissencephaly and it has also been associated with other neurological disorders such as epilepsy, schizophrenia and Alzheimer's disease (
  • Reln(+/-) knockout show neuronal migration defects that recapitulate the ones observed in the neocortex, hippocampus and cerebellum of the reeler mouse (
  • mice lacking EphB1 and EphB2 display a positioning defect of CA3 hippocampal pyramidal neurons, similar to that in Reelin-deficient mice, and this cell migration defect depends on the kinase activity of EphB proteins