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Reelin is a protein that helps regulate processes of neuronal migration and positioning in the developing brain. Besides this important role in early development, reelin continues to work in the adult brain. It modulates the synaptic plasticity by enhancing the induction and maintenance of long-term potentiation.[1][2] It also stimulates dendrite[3] and dendritic spine[4] development and regulates the continuing migration of neuroblasts generated in adult neurogenesis sites like subventricular and subgranular zones. It is found not only in the brain, but also in the spinal cord, blood, and other body organs and tissues.

Reelin has been suggested to be implicated in pathogenesis of several brain diseases. Significantly lowered expression of the protein have been found in schizophrenia and psychotic bipolar disorder, but the cause of it is uncertain as studies show that psychotropic medication itself affects RELN expression and the epigenetic hypothesis aimed at explaining the changed levels[5] has received some contradictory evidence.[6][7] Total lack of reelin causes a form of lissencephaly. Reelin also may play a role in Alzheimer's disease, temporal lobe epilepsy, and autism.

Overview

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Reelin's name comes from the abnormal reeling gait of reeler mice,[8] which were later found to have a deficiency of this brain protein and were homozygous for mutation of the RELN gene. The primary phenotype associated with loss of reelin function is a failure of neuronal positioning throughout the developing CNS. The mice heterozygous for the reelin gene, while having little neuroanatomical defects, display the endophenotypic traits linked to psychotic disorders.[9]

Discovery

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Video: the reeler mice mutants, first described in 1951 by D.S.Falconer, were later found to lack reelin protein.
Normal and Reeler mice brain slices.

Mutant mice provide insight into the underlying molecular mechanisms of the development of the CNS. Useful spontaneous mutations were first identified by scientists interested in motor behavior, and it proved relatively easy to screen littermates for mice that showed difficulties moving around the cage. A number of such mice were found and given descriptive names such as reeler, weaver, lurcher, nervous, and staggerer.

The "reeler" mouse was first described in the 1951 by D.S.Falconer[8] in Edinburgh University as a spontaneous variant arising in a colony of mice maintained by geneticist Charlotte Auerbach.[citation needed] Histopathological studies in the 1960s revealed that the cerebellum in reeler mice is dramatically decreased in size and the normal laminar organization found in several brain regions is disrupted.[10] The 1970s brought the discovery of cellular layers inversion in the mice neocortex,[11] which attracted more attention to the reeler mutation.

In 1994 a new allele of reeler was obtained by insertional mutagenesis (Miao et al., 1994). [12] This provided the first molecular marker of the locus, permitting the gene, RELN gene to be mapped to chromosome 7q22 and subsequently cloned and identified (D'Arcangelo et al., 1995).[13] Japanese scientists at Kochi Medical School successfully raised antibodies against normal brain extracts in reeler mice, later these antibodies were found to be specific monoclonal antibody for reelin, and were termed CR-50 (Cajal-Rezius marker 50).[14] They noted that CR-50 reacted specifically with Cajal-Retzius neurons, whose functional role was unknown until then.

The Reelin receptors, apolipoprotein E receptor 2 (ApoER2) and very-low-density lipoprotein receptor (VLDLR), were discovered by Trommsdorff, Herz and colleagues, who initially found that the cytosolic adaptor protein Dab1 interacts with the cytoplasmic domain of LDL receptor family members.[15] They then went on to show that the double knockout mice for ApoER2 and VLDLR, which both interact with Dab1, had cortical layering defects similar to those in reeler. this result implied that they were receptors it was the later papers that demonstrated Reelin binding that confirmed this identity.[16]

The downstream pathway of Reelin was further clarified using other mutant mice, including yotari and scrambler. These mutants have phenotypes similar to that of reeler but have no mutation in reelin. It was then demonstrated that the mouse disabled homologue 1 (Dab1) gene is responsible for the phenotypes of these mutant mice, as Dab1 protein was absent (yotari) or only barely (scrambler) detectable in these mutants.[17] Targeted disruption of Dab1 also caused a phenotype similar to that of reeler. Pinpointing the DAB1 as a pivotal regulator of the reelin signaling cascade started the tedious process of deciphering its complex interactions.

There followed a series of speculative reports linking reelin's genetic variation and interactions to schizophrenia, Alzheimer's disease, autism and other highly complex dysfunctions. These and other discoveries, coupled with the perspective of unraveling the evolutionary changes that allowed for the creation of human brain, highly intensified the research. As of 2008, some 13 years after the gene coding the protein was discovered, hundreds of scientific articles address the multiple aspects of its structure and functioning.[18] These aspects have been summarized by some of the researchers in a book called "Reelin Glycoprotein: Structure, Biology and Roles in Health and Disease" that saw print in 2008.[19]

Tissue distribution and secretion

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Studies show that Reelin is absent from synaptic vesicles and is secreted via constitutive secretory pathway, being stored in Golgi secretory vesicles.[20] Reelin's release rate is not regulated by depolarization, but strictly depends on its synthesis rate. This relationship is similar to that reported for the secretion of other ECM proteins.

During the brain development, reelin is secreted in the cortex and hippocampus by Cajal-Retzius cells, Cajal cells, and Retzius cells.[21] Reelin-expressing cells in the prenatal and early postnatal brain are predominantly found in the marginal zone (MZ) of the cortex and in the temporary subpial granular layer (SGL), which is manifested to the highest extent in human,[22] and in the hippocampal stratum lacunosum-moleculare and the upper marginal layer of the dentate gyrus.

In the developing cerebellum, Reelin is expressed first in the external granule cell layer (EGL) before the granule cell migration to the internal granule cell layer (IGL).[23]

Peaking just after the birth, the synthesis of reelin then goes down sharply and becomes more diffuse compared with the distinctly laminar expression in the developing brain. In the adult brain, Reelin is expressed by GABA-ergic interneurons of the cortex and glutamatergic cerebellar neurons,[24] and by the few extant Cajal-Retzius cells. Among GABAergic interneurons, Reelin seems to be detected predominantly in those expressing calretinin and calbindin, like bitufted, horizontal, and Martinotti cells, but not parvalbumin-expressing cells, like chandelier or basket neurons.[25][26] In the white matter, a minute proportion of interstitial neurons has also been found to stain positive for reelin expression.[27] Outside the brain, reelin is found in adult mammalian blood, liver, pituitary pars intermedia, and adrenal chromaffin cells.[28] In the liver, reelin is localized in hepatic stellate cells.[29] The expression of Reelin increases when the liver is damaged, and returns to normal following its repair.[30]

Schema of the Reelin protein

In the eyes reelin is secreted by retinal ganglion cells and is also found in the endothelial layer of the cornea.[31] Similar to liver, the expression increases after an injury.

The protein is also produced by the odontoblasts, cells at the margins of the dental pulp. Reelin is found here both during odontogenesis and in the mature tooth.[32] Some authors suggest that odontoblasts play an additional role as sensory cells able to transduce pain signals to the nervous endings.[33] According to the hypothesis, reelin participates in the process[19] by enhancing the contact between odontoblasts and the nerve terminals.[34]

References

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  1. ^ Weeber EJ, Beffert U, Jones C; et al. (2002). "Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning". J. Biol. Chem. 277 (42): 39944–52. doi:10.1074/jbc.M205147200. PMID 12167620. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  2. ^ D'Arcangelo G (2005). "Apoer2: a reelin receptor to remember". Neuron. 47 (4): 471–3. doi:10.1016/j.neuron.2005.08.001. PMID 16102527. {{cite journal}}: Unknown parameter |month= ignored (help)
  3. ^ Niu S, Renfro A, Quattrocchi CC, Sheldon M, D'Arcangelo G (2004). "Reelin promotes hippocampal dendrite development through the VLDLR/ApoER2-Dab1 pathway". Neuron. 41 (1): 71–84. doi:10.1016/S0896-6273(03)00819-5. PMID 14715136. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ Niu S, Yabut O, D'Arcangelo G (2008). "The Reelin signaling pathway promotes dendritic spine development in hippocampal neurons". The Journal of neuroscience : the official journal of the Society for Neuroscience. 28 (41): 10339–48. doi:10.1523/JNEUROSCI.1917-08.2008. PMID 18842893. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ {{cite web | url = http://www.schizophreniaforum.org/for/curr/grayson/default.asp | title = Current Hypotheses | author = Grayson DR, Guidotti A, Costa E | authorlink = | coauthors = | date = 2008-01-17 | format = | work = Schizophrenia Research Forum | publisher = schizophreniaforum.org | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-08-23}
  6. ^ Tochigi M, Iwamoto K, Bundo M, Komori A, Sasaki T, Kato N, Kato T (2007). "Methylation Status of the Reelin Promoter Region in the Brain of Schizophrenic Patients". Biological Psychiatry. 63: 530. doi:10.1016/j.biopsych.2007.07.003. PMID 17870056.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L, Jia P, Assadzadeh A, Flanagan J, Schumacher A, Wang SC, Petronis A (2008). "Epigenomic profiling reveals DNA-methylation changes associated with major psychosis". Am. J. Hum. Genet. 82 (3): 696–711. doi:10.1016/j.ajhg.2008.01.008. PMID 18319075.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ a b Falconer DS (1951), "Two new mutants, 'trembler' and 'reeler', with neurological actions in the house mouse (Mus musculus L.)" (PDF), Journal of Genetics, 50 (2): 192–201, doi:10.1007/BF02996215 {{citation}}: Unknown parameter |month= ignored (help)
  9. ^ Tueting P, Doueiri MS, Guidotti A, Davis JM, Costa E (2006). "Reelin down-regulation in mice and psychosis endophenotypes". Neurosci Biobehav Rev. 30 (8): 1065–77. doi:10.1016/j.neubiorev.2006.04.001. PMID 16769115.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ Hamburgh M (1963). "Analysis of the postnatal developmental effects of "reeler", a neurological mutation in mice. A study in developmental genetics". Dev. Biol. 19: 165–85. doi:10.1016/0012-1606(63)90040-X. PMID 14069672. {{cite journal}}: Unknown parameter |month= ignored (help)
  11. ^ Caviness VS (1976). "Patterns of cell and fiber distribution in the neocortex of the reeler mutant mouse". J. Comp. Neurol. 170 (4): 435–47. doi:10.1002/cne.901700404. PMID 1002868. {{cite journal}}: Unknown parameter |month= ignored (help)
  12. ^ Miao GG, Smeyne RJ, D'Arcangelo G, Copeland NG, Jenkins NA, Morgan JI, Curran T (1994). "Isolation of an allele of reeler by insertional mutagenesis". Proc. Natl. Acad. Sci. U.S.A. 91 (23): 11050–4. doi:10.1073/pnas.91.23.11050. PMC 45164. PMID 7972007. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ D'Arcangelo G, Miao GG, Chen SC, Soares HD, Morgan JI, Curran T (1995). "A protein related to extracellular matrix proteins deleted in the mouse mutant reeler". Nature. 374 (6524): 719–23. doi:10.1038/374719a0. PMID 7715726. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  14. ^ Ogawa M, Miyata T, Nakajima K; et al. (1995). "The reeler gene-associated antigen on Cajal-Retzius neurons is a crucial molecule for laminar organization of cortical neurons". Neuron. 14 (5): 899–912. doi:10.1016/0896-6273(95)90329-1. PMID 7748558. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  15. ^ Trommsdorff M, Borg JP, Margolis B, Herz J (1998). "Interaction of cytosolic adaptor proteins with neuronal apolipoprotein E receptors and the amyloid precursor protein". J. Biol. Chem. 273 (50): 33556–60. PMID 9837937. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ Trommsdorff M, Gotthardt M, Hiesberger T; et al. (1999). "Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2". Cell. 97 (6): 689–701. doi:10.1016/S0092-8674(00)80782-5. PMID 10380922. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  17. ^ Sheldon M, Rice DS, D'Arcangelo G; et al. (1997). "Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice". Nature. 389 (6652): 730–3. doi:10.1038/39601. PMID 9338784. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  18. ^ "Reelin" mentioned in the titles of scientific literature - a search in the Google Scholar
  19. ^ a b Hossein S. Fatemi, ed. (2008). Reelin Glycoprotein: Structure, Biology and Roles in Health and Disease. Springer. p. 444. ISBN 978-0-387-76760-4.
  20. ^ Lacor PN, Grayson DR, Auta J, Sugaya I, Costa E, Guidotti A (2000). "Reelin secretion from glutamatergic neurons in culture is independent from neurotransmitter regulation". Proc. Natl. Acad. Sci. U.S.A. 97 (7): 3556–61. doi:10.1073/pnas.050589597. PMC 16278. PMID 10725375. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  21. ^ Meyer G, Goffinet AM, Fairén A (1999). "What is a Cajal-Retzius cell? A reassessment of a classical cell type based on recent observations in the developing neocortex". Cereb. Cortex. 9 (8): 765–75. doi:10.1093/cercor/9.8.765. PMID 10600995. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  22. ^ Meyer G, Goffinet AM (1998). "Prenatal development of reelin-immunoreactive neurons in the human neocortex". J. Comp. Neurol. 397 (1): 29–40. doi:10.1002/(SICI)1096-9861(19980720)397:1<29::AID-CNE3>3.3.CO;2-7. PMID 9671277. {{cite journal}}: Unknown parameter |month= ignored (help)
  23. ^ Schiffmann SN, Bernier B, Goffinet AM (1997). "Reelin mRNA expression during mouse brain development". Eur. J. Neurosci. 9 (5): 1055–71. doi:10.1111/j.1460-9568.1997.tb01456.x. PMID 9182958. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  24. ^ Pesold C, Impagnatiello F, Pisu MG; et al. (1998). "Reelin is preferentially expressed in neurons synthesizing gamma-aminobutyric acid in cortex and hippocampus of adult rats". Proc. Natl. Acad. Sci. U.S.A. 95 (6): 3221–6. doi:10.1073/pnas.95.6.3221. PMC 19723. PMID 9501244. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  25. ^ Alcántara S, Ruiz M, D'Arcangelo G; et al. (1 October 1998). "Regional and cellular patterns of reelin mRNA expression in the forebrain of the developing and adult mouse". J. Neurosci. 18 (19): 7779–99. PMID 9742148. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  26. ^ Pesold C, Liu WS, Guidotti A, Costa E, Caruncho HJ (1999). "Cortical bitufted, horizontal, and Martinotti cells preferentially express and secrete reelin into perineuronal nets, nonsynaptically modulating gene expression". Proc. Natl. Acad. Sci. U.S.A. 96 (6): 3217–22. doi:10.1073/pnas.96.6.3217. PMC 15922. PMID 10077664. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  27. ^ Suárez-Solá ML, González-Delgado FJ, Pueyo-Morlans M, Medina-Bolívar OC, Hernández-Acosta NC, González-Gómez M, Meyer G (2009). "Neurons in the white matter of the adult human neocortex". Front Neuroanat. 3: 7. doi:10.3389/neuro.05.007.2009. PMC 2697018. PMID 19543540.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  28. ^ Smalheiser NR, Costa E, Guidotti A; et al. (2000). "Expression of reelin in adult mammalian blood, liver, pituitary pars intermedia, and adrenal chromaffin cells". Proc. Natl. Acad. Sci. U.S.A. 97 (3): 1281–6. doi:10.1073/pnas.97.3.1281. PMC 15597. PMID 10655522. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  29. ^ Samama B, Boehm N (2005). "Reelin immunoreactivity in lymphatics and liver during development and adult life". Anat Rec a Discov Mol Cell Evol Biol. 285 (1): 595–9. doi:10.1002/ar.a.20202. PMID 15912522. {{cite journal}}: Unknown parameter |month= ignored (help)
  30. ^ Kobold D, Grundmann A, Piscaglia F; et al. (2002). "Expression of reelin in hepatic stellate cells and during hepatic tissue repair: a novel marker for the differentiation of HSC from other liver myofibroblasts". J. Hepatol. 36 (5): 607–13. doi:10.1016/S0168-8278(02)00050-8. PMID 11983443. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  31. ^ Pulido JS, Sugaya I, Comstock J, Sugaya K (2007). "Reelin expression is upregulated following ocular tissue injury". Graefes Arch. Clin. Exp. Ophthalmol. 245 (6): 889–93. doi:10.1007/s00417-006-0458-4. PMID 17120005. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  32. ^ Buchaille R, Couble ML, Magloire H, Bleicher F (2000). "A substractive PCR-based cDNA library from human odontoblast cells: identification of novel genes expressed in tooth forming cells". Matrix biology : journal of the International Society for Matrix Biology. 19 (5): 421–30. PMID 10980418. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  33. ^ Allard B, Magloire H, Couble ML, Maurin JC, Bleicher F (2006). "Voltage-gated sodium channels confer excitability to human odontoblasts: possible role in tooth pain transmission". The Journal of biological chemistry. 281 (39): 29002–10. doi:10.1074/jbc.M601020200. PMID 16831873. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  34. ^ Maurin JC, Couble ML, Didier-Bazes M, Brisson C, Magloire H, Bleicher F (2004). "Expression and localization of reelin in human odontoblasts". Matrix biology : journal of the International Society for Matrix Biology. 23 (5): 277–85. doi:10.1016/j.matbio.2004.06.005. PMID 15464360. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)