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Gene Review

Reln  -  reelin

Mus musculus

Synonyms: Reeler protein, Reelin, Rl, reeler, rl
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Disease relevance of Reln

  • We hypothesized that human influenza infection in day 9 pregnant mice would alter the expression of reelin in day 0 neonatal brains [1].

Psychiatry related information on Reln

  • These results suggest a specific link between reelin-related neuronal pathology and dopamine involvement in the pathophysiology of psychotic disorders [2].
  • There is circumstantial evidence that the reelin signaling pathway may contribute to neurodegeneration in the adult brain and could be linked to Alzheimer's disease (AD) [3].
  • The +/rl mice showed a selective deficit in reversal learning, with a pattern of errors that suggested impaired visual attention rather than a deficiency in perseveration and inhibitory control [4].
  • These findings offer support for the more general hypothesis that down-regulation of reelin, of either genetic or epigenetic origin, through associated reductions in the OTRs, contributes to the deficiencies in social behavior that are characteristic of both schizophrenia and autism [5].

High impact information on Reln

  • CASK acts as a coactivator of Tbr-1 to induce transcription of T-element containing genes, including reelin, a gene that is essential for cerebrocortical development [6].
  • These processes are severely disrupted by mutations in reelin which cause widespread misplacement of neurons and associated ataxia in reeler mice [7].
  • In the cerebellum, adenosine receptors were absent in Weaver mice, which lack granule cells, and were displaced in Reeler mice, which have displacements of granule cells [8].
  • These results suggest that Reln regulates neuronal positioning by stimulating Dab1 tyrosine phosphorylation [9].
  • BDNF regulates reelin expression and Cajal-Retzius cell development in the cerebral cortex [10].

Biological context of Reln

  • We have found that the intracellular Dab1 protein receives a tyrosine phosphorylation signal from extracellular Reln protein [9].
  • Dab1 tyrosine phosphorylation sites and not downregulation of Dab1 protein are required for Reln signaling [11].
  • Complete loss of Dab1, however, recapitulates the Reln phenotype [11].
  • On the basis of the available genomic sequence from mouse Chromosome (Chr) 5, we concluded that the mPres gene is centromerically related to and resides within 19 kb of, the Reln gene [12].
  • These results reveal no effect of Reln gene dosage and provide significant challenges to both the Reln and the neurodevelopmental hypotheses of the etiology of major psychopathologies [13].

Anatomical context of Reln

  • During development, cells expressing Dab1 are located next to those secreting Reln at critical stages of formation of the cerebral cortex, cerebellum and hippocampus, before the first abnormalities in cell position become apparent in either reeler or scrambler [14].
  • Reln is a large extracellular protein secreted by Cajal-Retzius cells in the forebrain and by granule neurons in the cerebellum [14].
  • BACKGROUND: The extracellular protein Reln controls neuronal migrations in parts of the cortex, hippocampus and cerebellum [11].
  • The dysfunction of GABAergic interneurons observed in psychotic brains in combination with reduced Reln expression and downregulation of Reln-integrin receptor interaction, may provide an explanation for the reported decrease in neuropile expression including dendritic spine density reduction, in neocortex of schizophrenia patients [15].
  • Reelin (Reln) is expressed in specific GABAergic neurons in layer I and II of neocortex, and is secreted into the extracellular matrix where it surrounds dendrites, spines and neurite arborizations, and binds to integrin receptors located on post-synaptic densities of apical dendritic spines [15].

Associations of Reln with chemical compounds

  • Hypermethlyation of RELN and GAD67 promoters can be induced by treating mice with methionine, and these mice display brain and behavioral abnormalities similar to +/rl [16].
  • Interestingly, in the presence of tiagabine, a blocker of gamma-aminobutyric acid (GABA) re-uptake system, the probability that (rl/rl) mice showed LTP decreased significantly, thus suggesting an impaired GABAergic transmission in reeler mutants [17].
  • The N-methyl-d-aspartic acid (NMDA) receptor antagonist d-(-)-2 amino-5-phosphonopentanoic acid prevented the induction of LTP in (rl/rl) mice, thus confirming that this form of synaptic plasticity was NMDA receptor-dependent [17].
  • Interestingly, the increased AMPAR response after reelin application was not blocked by PP1 but was blocked by the phosphoinositide-3' kinase (PI3K) inhibitors wortmannin and LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride] [18].
  • The finding of a high receptor density in the Purkinje cell masses of the rl/rl mutant, where Purkinje cells are devoid of afferent basket cell input, suggests that benzodiazepine receptors are expressed and maintained in the absence of a full complement of GABAergic afferents [19].

Physical interactions of Reln


Regulatory relationships of Reln

  • The reeler heterozygous mouse (+/rl) appears superficially normal but has been of interest as an animal model for psychosis since the discovery that reelin is 50% down-regulated in postmortem psychotic brain [16].
  • To examine whether Dnmt1 regulates reelin gene expression, we used an antisense approach to reduce (knock down) Dnmt1 expression [21].
  • At prenatal stages, reelin was also expressed in the olfactory bulb, and striatum and in restricted nuclei in the ventral telencephalon, hypothalamus, thalamus, and pretectum [22].
  • The addition of reelin (2-40 pM) to SNSs enhances the incorporation of [(35)S]methionine into Arc and other rapidly translated proteins in a concentration-dependent manner [23].

Other interactions of Reln

  • This mutant protein is not tyrosine phosphorylated during brain development and is not upregulated to the extent observed in the Reln or the apoER2 and VLDLR receptor mutants [11].
  • Recent findings indicate that the reelin (RELN) and GAD67 promoters are hypermethylated in GABAergic neurons of psychotic postmortem brain and that DNA methyltransferase 1 (DNMT1) is up-regulated [16].
  • 5. Tbr1(+) cells in the marginal zone were almost always reelin(+) [24].
  • Consistent with this view, a decreased density of parvalbumin-positive GABAergic striatal interneurons was found in (rl/rl) mice in comparison to (+/+) mice [17].
  • CDK-5 activity was similar in mice lacking Reln, ApoE, or both [20].
  • PI3K and Akt are required for the effects of Reelin on the organization of the cortical plate, but their downstream partners mTor and glycogen synthase kinase 3beta (GSK3beta) are not [25].

Analytical, diagnostic and therapeutic context of Reln

  • 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 [26].
  • Here we show that a repetitive electrical stimulation of the cortico-striatal pathway elicited long-term potentiation (LTP) in homozygous reeler (rl/rl) mice, while causing long-term depression in their wild-type (+/+) littermates [17].
  • To gain insights into the functions of Reelin, we performed high-resolution in situ hybridization analyses to determine the pattern of reelin expression in the developing forebrain of the mouse [22].
  • Furthermore, expression of mRNA and protein of reelin was verified by Northern blotting and immunohistochemistry using a CR-50 monoclonal antibody (mAb) which is specific to Reelin, the reelin gene product [27].
  • Southern blot analysis using a probe derived from the D5Gmr1 locus revealed no gross structural rearrangement in the rl locus [28].


  1. Defective corticogenesis and reduction in Reelin immunoreactivity in cortex and hippocampus of prenatally infected neonatal mice. Fatemi, S.H., Emamian, E.S., Kist, D., Sidwell, R.W., Nakajima, K., Akhter, P., Shier, A., Sheikh, S., Bailey, K. Mol. Psychiatry (1999) [Pubmed]
  2. Preferential alterations in the mesolimbic dopamine pathway of heterozygous reeler mice: an emerging animal-based model of schizophrenia. Ballmaier, M., Zoli, M., Leo, G., Agnati, L.F., Spano, P. Eur. J. Neurosci. (2002) [Pubmed]
  3. Reelin in plaques of beta-amyloid precursor protein and presenilin-1 double-transgenic mice. Wirths, O., Multhaup, G., Czech, C., Blanchard, V., Tremp, G., Pradier, L., Beyreuther, K., Bayer, T.A. Neurosci. Lett. (2001) [Pubmed]
  4. Executive functions in the heterozygous reeler mouse model of schizophrenia. Brigman, J.L., Padukiewicz, K.E., Sutherland, M.L., Rothblat, L.A. Behav. Neurosci. (2006) [Pubmed]
  5. Oxytocin receptors in brain cortical regions are reduced in haploinsufficient (+/-) reeler mice. Liu, W., Pappas, G.D., Carter, C.S. Neurol. Res. (2005) [Pubmed]
  6. Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2. Hsueh, Y.P., Wang, T.F., Yang, F.C., Sheng, M. Nature (2000) [Pubmed]
  7. Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice. Sheldon, M., Rice, D.S., D'Arcangelo, G., Yoneshima, H., Nakajima, K., Mikoshiba, K., Howell, B.W., Cooper, J.A., Goldowitz, D., Curran, T. Nature (1997) [Pubmed]
  8. Adenosine receptors: autoradiographic evidence for their location on axon terminals of excitatory neurons. Goodman, R.R., Kuhar, M.J., Hester, L., Snyder, S.H. Science (1983) [Pubmed]
  9. Reelin-induced tryosine phosphorylation of disabled 1 during neuronal positioning. Howell, B.W., Herrick, T.M., Cooper, J.A. Genes Dev. (1999) [Pubmed]
  10. BDNF regulates reelin expression and Cajal-Retzius cell development in the cerebral cortex. Ringstedt, T., Linnarsson, S., Wagner, J., Lendahl, U., Kokaia, Z., Arenas, E., Ernfors, P., Ibáñez, C.F. Neuron (1998) [Pubmed]
  11. Dab1 tyrosine phosphorylation sites relay positional signals during mouse brain development. Howell, B.W., Herrick, T.M., Hildebrand, J.D., Zhang, Y., Cooper, J.A. Curr. Biol. (2000) [Pubmed]
  12. Genomic characterization and expression of mouse prestin, the motor protein of outer hair cells. Zheng, J., Long, K.B., Matsuda, K.B., Madison, L.D., Ryan, A.D., Dallos, P.D. Mamm. Genome (2003) [Pubmed]
  13. Behavioral phenotype of the reeler mutant mouse: effects of RELN gene dosage and social isolation. Salinger, W.L., Ladrow, P., Wheeler, C. Behav. Neurosci. (2003) [Pubmed]
  14. Disabled-1 acts downstream of Reelin in a signaling pathway that controls laminar organization in the mammalian brain. Rice, D.S., Sheldon, M., D'Arcangelo, G., Nakajima, K., Goldowitz, D., Curran, T. Development (1998) [Pubmed]
  15. New neurochemical markers for psychosis: a working hypothesis of their operation. Guidotti, A., Pesold, C., Costa, E. Neurochem. Res. (2000) [Pubmed]
  16. Reelin down-regulation in mice and psychosis endophenotypes. Tueting, P., Doueiri, M.S., Guidotti, A., Davis, J.M., Costa, E. Neuroscience and biobehavioral reviews (2006) [Pubmed]
  17. Altered cortico-striatal synaptic plasticity and related behavioural impairments in reeler mice. Marrone, M.C., Marinelli, S., Biamonte, F., Keller, F., Sgobio, C.A., Ammassari-Teule, M., Bernardi, G., Mercuri, N.B. Eur. J. Neurosci. (2006) [Pubmed]
  18. Differential reelin-induced enhancement of NMDA and AMPA receptor activity in the adult hippocampus. Qiu, S., Zhao, L.F., Korwek, K.M., Weeber, E.J. J. Neurosci. (2006) [Pubmed]
  19. Cerebellar benzodiazepine receptors: cellular localization and consequences of neurological mutations in mice. Rotter, A., Frostholm, A. Brain Res. (1988) [Pubmed]
  20. Apolipoprotein E and Reelin ligands modulate tau phosphorylation through an apolipoprotein E receptor/disabled-1/glycogen synthase kinase-3beta cascade. Ohkubo, N., Lee, Y.D., Morishima, A., Terashima, T., Kikkawa, S., Tohyama, M., Sakanaka, M., Tanaka, J., Maeda, N., Vitek, M.P., Mitsuda, N. FASEB J. (2003) [Pubmed]
  21. DNA methyltransferase 1 regulates reelin mRNA expression in mouse primary cortical cultures. Noh, J.S., Sharma, R.P., Veldic, M., Salvacion, A.A., Jia, X., Chen, Y., Costa, E., Guidotti, A., Grayson, D.R. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  22. Regional and cellular patterns of reelin mRNA expression in the forebrain of the developing and adult mouse. Alcántara, S., Ruiz, M., D'Arcangelo, G., Ezan, F., de Lecea, L., Curran, T., Sotelo, C., Soriano, E. J. Neurosci. (1998) [Pubmed]
  23. A reelin-integrin receptor interaction regulates Arc mRNA translation in synaptoneurosomes. Dong, E., Caruncho, H., Liu, W.S., Smalheiser, N.R., Grayson, D.R., Costa, E., Guidotti, A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  24. Cajal-Retzius cells in the mouse: transcription factors, neurotransmitters, and birthdays suggest a pallial origin. Hevner, R.F., Neogi, T., Englund, C., Daza, R.A., Fink, A. Brain Res. Dev. Brain Res. (2003) [Pubmed]
  25. Reelin signals through phosphatidylinositol 3-kinase and Akt to control cortical development and through mTor to regulate dendritic growth. Jossin, Y., Goffinet, A.M. Mol. Cell. Biol. (2007) [Pubmed]
  26. The reelin receptor ApoER2 recruits JNK-interacting proteins-1 and -2. Stockinger, W., Brandes, C., Fasching, D., Hermann, M., Gotthardt, M., Herz, J., Schneider, W.J., Nimpf, J. J. Biol. Chem. (2000) [Pubmed]
  27. A novel neurological mutant mouse, yotari, which exhibits reeler-like phenotype but expresses CR-50 antigen/reelin. Yoneshima, H., Nagata, E., Matsumoto, M., Yamada, M., Nakajima, K., Miyata, T., Ogawa, M., Mikoshiba, K. Neurosci. Res. (1997) [Pubmed]
  28. Isolation of an allele of reeler by insertional mutagenesis. Miao, G.G., Smeyne, R.J., D'Arcangelo, G., Copeland, N.G., Jenkins, N.A., Morgan, J.I., Curran, T. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
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