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Gene Review

RELN  -  reelin

Homo sapiens

Synonyms: LIS2, PRO1598, RL, Reelin
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Disease relevance of RELN

  • One of the genes identified, RELN (Reelin), a key regulator of neuronal migration, is frequently silenced in pancreatic cancers, as are several of its downstream mediators [1].
  • Autosomal recessive lissencephaly with cerebellar hypoplasia, accompanied by severe delay, hypotonia, and seizures, has been associated with mutations of the reelin (RELN) gene [2].
  • In the retina of embryos and alevins, RELN immunoreactivity is detected in cells of the ganglion cell layer (GCL) and inner nuclear layer (INL), and in the inner plexiform layer (IPL), where it appears as "diffuse" material confined to the ON-sublayer [3].
  • In one family, the association of cortical dysplasia and congenital lymphedema have been related to mutations in the RELN gene [4].
  • Here, we have analysed two major components of the reelin pathway involved in neuronal migration and cortical development, that is, p35 and disabled-1 (dab1), in gangliogliomas [5].

Psychiatry related information on RELN


High impact information on RELN

  • Role of the reelin signaling pathway in central nervous system development [10].
  • The reeler phenotype thus seems to reflect a failure of early events associated with brain lamination which are normally controlled by reelin [11].
  • Apoer2: a reelin receptor to remember [12].
  • Moreover, a number of studies indicate that CR cells, and their secreted gene product, reelin, are involved in neuronal migration by acting on two key partners, migrating neurons and radial glial cells [13].
  • Increased cell motility was also induced by knockdown of downstream components of the RELN pathway, including ApoER2, VLDLR, and DAB1 [1].

Chemical compound and disease context of RELN


Biological context of RELN

  • Differential and epigenetic gene expression profiling identifies frequent disruption of the RELN pathway in pancreatic cancers [1].
  • Importantly, small interfering RNA-mediated knockdown of RELN in pancreatic cancer cells that retain RELN expression resulted in greatly enhanced cell motility, invasiveness, and colony-forming ability [1].
  • We further determined the cellular expression of the proteins RELN and DAB1 in 50 human brains ranging in age from 10 gestational weeks (GW) to 62 years using immunochemistry [16].
  • We genotyped all four WNT2 polymorphisms and a polymorphic trinucleotide repeat in the 5' UTR of RELN in 107 families with multiple autistic children, and evaluated evidence for association between these variants and autism by the transmission disequilibrium test (TDT) [17].
  • Our interpretation of these findings is that it is unlikely that DNA variations in RELN and WNT2 play a significant role in the genetic predisposition to autism [17].

Anatomical context of RELN

  • RELN mRNA was preferentially expressed in GABAergic interneurons of PFC, temporal cortex, hippocampus, and glutamatergic granule cells of cerebellum [7].
  • We found that Reln is expressed predominantly in layer I of both cortices and is localized to bitufted (double-bouquet), horizontal, and multipolar gamma-aminobutyric acid-ergic interneurons, which secrete Reln into extracellular matrix [18].
  • Colocalization of integrin receptors and reelin in dendritic spine postsynaptic densities of adult nonhuman primate cortex [18].
  • Expression and localization of reelin in human odontoblasts [19].
  • This alternative reelin is generally expressed in the same cells as the major form, but is almost undetectable in retina and spinal cord [20].

Associations of RELN with chemical compounds

  • In addition, the mRNA encoding the methylating enzyme, DNA methyltransferase 1, is up-regulated in the same neurons that coexpress reelin and glutamic acid decarboxylase 67 [21].
  • The histone deacetylase inhibitors trichostatin A (TSA) and valproic acid also induced expression of the endogenous reelin promoter, although TSA was considerably more potent [22].
  • RA-induced differentiation was also associated with demethylation of the reelin promoter [22].
  • Retinoic acid (RA)-induced differentiation of NT2 cells to hNT neurons was accompanied by increased reelin expression and by the appearance of three DNase I hypersensitive sites 5' to the RNA start site [22].
  • Here, we review the molecular mechanisms through which APOE, cholesterol, reelin and APOE receptors control synaptic functions that are essential for cognition, learning, memory, behaviour and neuronal survival [23].

Physical interactions of RELN

  • We examined the expression of DISC1 and these selected binding partners as well as reelin, a protein in a related signaling pathway, in the hippocampus and dorsolateral prefrontal cortex of postmortem human brain patients with schizophrenia and controls [24].

Regulatory relationships of RELN


Other interactions of RELN

  • In the same samples of temporal cortex, we found a decrease in RELN protein of approximately 50% but no changes in DAB1 protein expression [7].
  • CONCLUSIONS: The high prevalence of the silencing of RELN pathway components and its reversal by histone deacetylase inhibitors suggest the importance of this pathway as a diagnostic and therapeutic target for pancreatic cancer [1].
  • Group differences were absent for DAB1,GAD(65) and neuron-specific-enolase expression implying that RELN and GAD(67) down-regulations were unrelated to neuronal damage [6].
  • CONCLUSIONS: Reductions in Reelin protein and mRNA and Dab 1 mRNA and elevations in Reln receptor VLDLR mRNA demonstrate impairments in the Reelin signaling system in autism, accounting for some of the brain structural and cognitive deficits observed in the disorder [27].
  • Tests for association in Duke and AGRE families were also performed on four additional SNPs in the genes PSMC2 and ORC5L, which flank RELN [28].

Analytical, diagnostic and therapeutic context of RELN


  1. Differential and epigenetic gene expression profiling identifies frequent disruption of the RELN pathway in pancreatic cancers. Sato, N., Fukushima, N., Chang, R., Matsubayashi, H., Goggins, M. Gastroenterology (2006) [Pubmed]
  2. Genetic malformations of cortical development. Guerrini, R., Marini, C. Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale. (2006) [Pubmed]
  3. Reelin expression in the retina and optic tectum of developing common brown trout. Candal, E.M., Caruncho, H.J., Sueiro, C., Anadón, R., Rodríguez-Moldes, I. Brain Res. Dev. Brain Res. (2005) [Pubmed]
  4. Aplasia cutis congenita, skull defect, brain heterotopia, and intestinal lymphangiectasia. Bonioli, E., Hennekam, R.C., Spena, G., Morcaldi, G., Di Stefano, A., Serra, G., Bellini, C. Am. J. Med. Genet. A (2005) [Pubmed]
  5. The reelin pathway components disabled-1 and p35 in gangliogliomas--a mutation and expression analysis. Kam, R., Chen, J., Blümcke, I., Normann, S., Fassunke, J., Elger, C.E., Schramm, J., Wiestler, O.D., Becker, A.J. Neuropathol. Appl. Neurobiol. (2004) [Pubmed]
  6. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Guidotti, A., Auta, J., Davis, J.M., Di-Giorgi-Gerevini, V., Dwivedi, Y., Grayson, D.R., Impagnatiello, F., Pandey, G., Pesold, C., Sharma, R., Uzunov, D., Costa, E., DiGiorgi Gerevini, V. Arch. Gen. Psychiatry (2000) [Pubmed]
  7. A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Impagnatiello, F., Guidotti, A.R., Pesold, C., Dwivedi, Y., Caruncho, H., Pisu, M.G., Uzunov, D.P., Smalheiser, N.R., Davis, J.M., Pandey, G.N., Pappas, G.D., Tueting, P., Sharma, R.P., Costa, E. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  8. Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Persico, A.M., D'Agruma, L., Maiorano, N., Totaro, A., Militerni, R., Bravaccio, C., Wassink, T.H., Schneider, C., Melmed, R., Trillo, S., Montecchi, F., Palermo, M., Pascucci, T., Puglisi-Allegra, S., Reichelt, K.L., Conciatori, M., Marino, R., Quattrocchi, C.C., Baldi, A., Zelante, L., Gasparini, P., Keller, F. Mol. Psychiatry (2001) [Pubmed]
  9. Altered levels of cerebrospinal fluid reelin in frontotemporal dementia and Alzheimer's disease. Sáez-Valero, J., Costell, M., Sjögren, M., Andreasen, N., Blennow, K., Luque, J.M. J. Neurosci. Res. (2003) [Pubmed]
  10. Role of the reelin signaling pathway in central nervous system development. Rice, D.S., Curran, T. Annu. Rev. Neurosci. (2001) [Pubmed]
  11. A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. D'Arcangelo, G., Miao, G.G., Chen, S.C., Soares, H.D., Morgan, J.I., Curran, T. Nature (1995) [Pubmed]
  12. Apoer2: a reelin receptor to remember. D'Arcangelo, G. Neuron (2005) [Pubmed]
  13. The cells of cajal-retzius: still a mystery one century after. Soriano, E., Del Río, J.A. Neuron (2005) [Pubmed]
  14. S-adenosyl methionine and DNA methyltransferase-1 mRNA overexpression in psychosis. Guidotti, A., Ruzicka, W., Grayson, D.R., Veldic, M., Pinna, G., Davis, J.M., Costa, E. Neuroreport (2007) [Pubmed]
  15. Gangliogliomas: an intriguing tumor entity associated with focal epilepsies. Blümcke, I., Wiestler, O.D. J. Neuropathol. Exp. Neurol. (2002) [Pubmed]
  16. Reelin and disabled-1 expression in developing and mature human cortical neurons. Deguchi, K., Inoue, K., Avila, W.E., Lopez-Terrada, D., Antalffy, B.A., Quattrocchi, C.C., Sheldon, M., Mikoshiba, K., D'Arcangelo, G., Armstrong, D.L. J. Neuropathol. Exp. Neurol. (2003) [Pubmed]
  17. Lack of evidence for an association between WNT2 and RELN polymorphisms and autism. Li, J., Nguyen, L., Gleason, C., Lotspeich, L., Spiker, D., Risch, N., Myers, R.M. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2004) [Pubmed]
  18. Colocalization of integrin receptors and reelin in dendritic spine postsynaptic densities of adult nonhuman primate cortex. Rodriguez, M.A., Pesold, C., Liu, W.S., Kriho, V., Guidotti, A., Pappas, G.D., Costa, E. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  19. Expression and localization of reelin in human odontoblasts. Maurin, J.C., Couble, M.L., Didier-Bazes, M., Brisson, C., Magloire, H., Bleicher, F. Matrix Biol. (2004) [Pubmed]
  20. Evolutionarily conserved, alternative splicing of reelin during brain development. Lambert de Rouvroit, C., Bernier, B., Royaux, I., de Bergeyck, V., Goffinet, A.M. Exp. Neurol. (1999) [Pubmed]
  21. Reelin promoter hypermethylation in schizophrenia. Grayson, D.R., Jia, X., Chen, Y., Sharma, R.P., Mitchell, C.P., Guidotti, A., Costa, E. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  22. On the epigenetic regulation of the human reelin promoter. Chen, Y., Sharma, R.P., Costa, R.H., Costa, E., Grayson, D.R. Nucleic Acids Res. (2002) [Pubmed]
  23. Reelin, lipoprotein receptors and synaptic plasticity. Herz, J., Chen, Y. Nat. Rev. Neurosci. (2006) [Pubmed]
  24. Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs. Lipska, B.K., Peters, T., Hyde, T.M., Halim, N., Horowitz, C., Mitkus, S., Weickert, C.S., Matsumoto, M., Sawa, A., Straub, R.E., Vakkalanka, R., Herman, M.M., Weinberger, D.R., Kleinman, J.E. Hum. Mol. Genet. (2006) [Pubmed]
  25. Reelin expression during embryonic brain development in lacertilian lizards. Goffinet, A.M., Bar, I., Bernier, B., Trujillo, C., Raynaud, A., Meyer, G. J. Comp. Neurol. (1999) [Pubmed]
  26. GABAergic cortical neuron chromatin as a putative target to treat schizophrenia vulnerability. Costa, E., Grayson, D.R., Mitchell, C.P., Tremolizzo, L., Veldic, M., Guidotti, A. Critical reviews in neurobiology. (2003) [Pubmed]
  27. Reelin signaling is impaired in autism. Fatemi, S.H., Snow, A.V., Stary, J.M., Araghi-Niknam, M., Reutiman, T.J., Lee, S., Brooks, A.I., Pearce, D.A. Biol. Psychiatry (2005) [Pubmed]
  28. Analysis of the RELN gene as a genetic risk factor for autism. Skaar, D.A., Shao, Y., Haines, J.L., Stenger, J.E., Jaworski, J., Martin, E.R., DeLong, G.R., Moore, J.H., McCauley, J.L., Sutcliffe, J.S., Ashley-Koch, A.E., Cuccaro, M.L., Folstein, S.E., Gilbert, J.R., Pericak-Vance, M.A. Mol. Psychiatry (2005) [Pubmed]
  29. The human reelin gene: isolation, sequencing, and mapping on chromosome 7. DeSilva, U., D'Arcangelo, G., Braden, V.V., Chen, J., Miao, G.G., Curran, T., Green, E.D. Genome Res. (1997) [Pubmed]
  30. Analysis of reelin as a candidate gene for autism. Bonora, E., Beyer, K.S., Lamb, J.A., Parr, J.R., Klauck, S.M., Benner, A., Paolucci, M., Abbott, A., Ragoussis, I., Poustka, A., Bailey, A.J., Monaco, A.P. Mol. Psychiatry (2003) [Pubmed]
  31. Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: a preliminary report. Abdolmaleky, H.M., Cheng, K.H., Russo, A., Smith, C.L., Faraone, S.V., Wilcox, M., Shafa, R., Glatt, S.J., Nguyen, G., Ponte, J.F., Thiagalingam, S., Tsuang, M.T. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2005) [Pubmed]
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