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Besides this important role in the early period, reelin continues to work in the adult brain. It modulates the [[synaptic plasticity]] by enhancing [[Long-term potentiation|LTP]] induction and maintenance.<!--
Besides this important role in the early period, reelin continues to work in the adult brain. It modulates the [[synaptic plasticity]] by enhancing [[Long-term potentiation|LTP]] induction and maintenance.<!--


--><ref name="LTP1">Weeber, E. J., U. Beffert, C. Jones, J. M. Christian, E. Forster, J. D. Sweatt, and J. Herz. 2002. ''Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning.'' J. Biol. Chem. 277:39944-39952. PMID 12167620</ref><ref name="LTP2">D'Arcangelo G. (2005) ''Apoer2: a reelin receptor to remember.'' Neuron. 47(4):471-3. PMID 16102527</ref> It also stimulates dendrite development<!--
--><ref name="LTP1">{{cite journal |author=Weeber EJ, Beffert U, Jones C, ''et al'' |title=Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning |journal=J. Biol. Chem. |volume=277 |issue=42 |pages=39944–52 |year=2002 |month=October |pmid=12167620 |doi=10.1074/jbc.M205147200 |url=}}W</ref><ref name="LTP2">{{cite journal |author=D'Arcangelo G |title=Apoer2: a reelin receptor to remember |journal=Neuron |volume=47 |issue=4 |pages=471–3 |year=2005 |month=August |pmid=16102527 |doi=10.1016/j.neuron.2005.08.001 |url=}}</ref> It also stimulates dendrite development<!--


--><ref name="Niu_2004">Niu S, Renfro A, Quattrocchi CC, Sheldon M, D’Arcangelo G. (2004) ''Reelin promotes hippocampal dendrite development through the VLDLR/ApoER2-Dab1 pathway.'' Neuron. 2004 Jan 8;41(1):71-84. PMID 14715136 </ref><!--
--><ref name="Niu_2004">{{cite journal |author=Niu S, Renfro A, Quattrocchi CC, Sheldon M, D'Arcangelo G |title=Reelin promotes hippocampal dendrite development through the VLDLR/ApoER2-Dab1 pathway |journal=Neuron |volume=41 |issue=1 |pages=71–84 |year=2004 |month=January |pmid=14715136 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0896627303008195}}</ref><!--


--> and regulates the continuing migration of [[neuroblast]]s generated in [[adult neurogenesis]] sites like [[subventricular zone|subventricular]] and [[subgranular zone]]s.
--> and regulates the continuing migration of [[neuroblast]]s generated in [[adult neurogenesis]] sites like [[subventricular zone|subventricular]] and [[subgranular zone]]s.
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Mutant mice provide insight into the underlying molecular mechanisms of the development of the [[Central nervous system|CNS]]. These spontaneous mutations were first identified by scientists interested in motor behavior, and it proved relatively easy to screen [[littermate]]s 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.
Mutant mice provide insight into the underlying molecular mechanisms of the development of the [[Central nervous system|CNS]]. These spontaneous mutations were first identified by scientists interested in motor behavior, and it proved relatively easy to screen [[littermate]]s 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]] edition of [[Journal of Genetics]] by [[Douglas Scott Falconer]].<ref name="falconer"/> Histopathological studies in the 1960's revealed that the reeler cerebellum is dramatically decreased in size and the normal laminar organization found in several brain regions is disrupted.<ref name="hamburgh"> 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. PMID 14069672 </ref> 1970's brought the discovery of cellular layers inversion in the mice neocortex<ref name="caviness">Caviness VS Jr. (1976) ''Patterns of cell and fiber distribution in the neocortex of the reeler mutant mouse.'' J Comp Neurol. 170(4):435-47. PMID 1002868</ref>, which attracted more attention to the reeler mutation.
The "[[reeler]]" mouse was first described in the [[1951]] edition of [[Journal of Genetics]] by [[Douglas Scott Falconer]].<ref name="falconer"/> Histopathological studies in the 1960's revealed that the reeler cerebellum is dramatically decreased in size and the normal laminar organization found in several brain regions is disrupted.<ref name="hamburgh">{{cite journal |author=Hamburgh M |title=Analysis of the postnatal developmental effects of "reeler", a neurological mutation in mice. A study in developmental genetics |journal=Dev. Biol. |volume=19 |issue= |pages=165–85 |year=1963 |month=October |pmid=14069672 |doi= |url=}}</ref> 1970's brought the discovery of cellular layers inversion in the mice neocortex<ref name="caviness">{{cite journal |author=Caviness VS |title=Patterns of cell and fiber distribution in the neocortex of the reeler mutant mouse |journal=J. Comp. Neurol. |volume=170 |issue=4 |pages=435–47 |year=1976 |month=December |pmid=1002868 |doi=10.1002/cne.901700404 |url=}}</ref>, which attracted more attention to the reeler mutation.


In [[1995]], the RELN gene and protein were discovered at chromosome 7q22 by Gabriella D'Arcangelo and colleagues<ref name="Darcan1">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: 719-723. PMID 7715726</ref>. Almost immediately, Japanese scientists at [[Kochi Medical School]] had successfully created the first [[Monoclonal antibodies|monoclonal antibody]] for reelin, called CR-50.<ref name="cr50">Ogawa M, Miyata T, Nakajima K, Yagyu K, Seike M, Ikenaka K, Yamamoto H, Mikoshiba K. (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. PMID 7748558</ref> They noted that CR-50 reacted specifically with [[Cajal-Retzius cell|Cajal-Retzius neurons]], whose functional role was unknown till then.
In [[1995]], the RELN gene and protein were discovered at chromosome 7q22 by Gabriella D'Arcangelo and colleagues<ref name="Darcan1">{{cite journal |author=D'Arcangelo G, Miao GG, Chen SC, Soares HD, Morgan JI, Curran T |title=A protein related to extracellular matrix proteins deleted in the mouse mutant reeler |journal=Nature |volume=374 |issue=6524 |pages=719–23 |year=1995 |month=April |pmid=7715726 |doi=10.1038/374719a0 |url=}}</ref>. Almost immediately, Japanese scientists at [[Kochi Medical School]] had successfully created the first [[Monoclonal antibodies|monoclonal antibody]] for reelin, called CR-50.<ref name="cr50">{{cite journal |author=Ogawa M, Miyata T, Nakajima K, ''et al'' |title=The reeler gene-associated antigen on Cajal-Retzius neurons is a crucial molecule for laminar organization of cortical neurons |journal=Neuron |volume=14 |issue=5 |pages=899–912 |year=1995 |month=May |pmid=7748558 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/0896-6273(95)90329-1}}</ref> They noted that CR-50 reacted specifically with [[Cajal-Retzius cell|Cajal-Retzius neurons]], whose functional role was unknown till then.


The downstream pathway of Reelin was clarified using other mutant mice, including [[yotari]] and [[Scrambler mouse|scrambler]]. These mice have phenotypes similar to that of reeler but have no mutation in reelin. It was then demonstrated that the mouse ''disabled homologue 1'' ([[DAB1|Dab1]]) gene, which encodes a homolog of ''Drosophila disabled'', is the gene responsible for the phenotypes of these mutant mice, and Dab1 protein was absent (yotari) or only barely (scrambler) detectable in these mutants.<ref name="yotari_and_scrambler">Sheldon M, Rice DS, D'Arcangelo G, Yoneshima H, Nakajima K, Mikoshiba K, Howell BW, Cooper JA, Goldowitz D, Curran T. (1997) Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice. Nature. 389(6652):730-3. PMID 9338784 </ref> Targeted disruption of Dab1 also caused a phenotype similar to that of reeler.
The downstream pathway of Reelin was clarified using other mutant mice, including [[yotari]] and [[Scrambler mouse|scrambler]]. These mice have phenotypes similar to that of reeler but have no mutation in reelin. It was then demonstrated that the mouse ''disabled homologue 1'' ([[DAB1|Dab1]]) gene, which encodes a homolog of ''Drosophila disabled'', is the gene responsible for the phenotypes of these mutant mice, and Dab1 protein was absent (yotari) or only barely (scrambler) detectable in these mutants.<ref name="yotari_and_scrambler">{{cite journal |author=Sheldon M, Rice DS, D'Arcangelo G, ''et al'' |title=Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice |journal=Nature |volume=389 |issue=6652 |pages=730–3 |year=1997 |month=October |pmid=9338784 |doi=10.1038/39601 |url=}}</ref> Targeted disruption of Dab1 also caused a phenotype similar to that of reeler.




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|}
|}


The Reelin receptors, apolipoprotein E receptor 2 and very-low-density lipoprotein receptor, were discovered serendipitously by Trommsdorff et al, who found that the double [[Gene knockout|knockout]] mice for apolipoprotein E receptor 2 and very-low-density lipoprotein receptor, which they generated for another experiment, showed defects in cortical layering similar to that in reeler.<ref name="receptors_discovery">Trommsdorff M, Gotthardt M, Hiesberger T, Shelton J, Stockinger W, Nimpf J, Hammer RE, Richardson JA, Herz J. (1997) Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell. 97(6):689-701. PMID 10380922</ref>
The Reelin receptors, apolipoprotein E receptor 2 and very-low-density lipoprotein receptor, were discovered serendipitously by Trommsdorff et al, who found that the double [[Gene knockout|knockout]] mice for apolipoprotein E receptor 2 and very-low-density lipoprotein receptor, which they generated for another experiment, showed defects in cortical layering similar to that in reeler.<ref name="receptors_discovery">{{cite journal |author=Trommsdorff M, Gotthardt M, Hiesberger T, ''et al'' |title=Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2 |journal=Cell |volume=97 |issue=6 |pages=689–701 |year=1999 |month=June |pmid=10380922 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(00)80782-5}}</ref>


In the July of 2006, a group of Japanese scientists published the first report of [[X-ray crystallography]] and [[electron tomography]] investigation of reelin structure.<ref name="reelinstructure2006japan"/>
In the July of 2006, a group of Japanese scientists published the first report of [[X-ray crystallography]] and [[electron tomography]] investigation of reelin structure.<ref name="reelinstructure2006japan"/>


==Secretion and localization of reelin==
==Secretion and localization of reelin==
Studies show that Reelin is absent from [[synaptic vesicle]]s and is secreted via [[secretory pathway|constitutive secretory pathway]], being stored in [[Golgi apparatus|Golgi]] secretory vesicles.<ref name="golgi">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. PMID 10725375 [http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=10725375 free full text]</ref> 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 [[Extracellular matrix|ECM]] proteins.
Studies show that Reelin is absent from [[synaptic vesicle]]s and is secreted via [[secretory pathway|constitutive secretory pathway]], being stored in [[Golgi apparatus|Golgi]] secretory vesicles.<ref name="golgi">{{cite journal |author=Lacor PN, Grayson DR, Auta J, Sugaya I, Costa E, Guidotti A |title=Reelin secretion from glutamatergic neurons in culture is independent from neurotransmitter regulation |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue=7 |pages=3556–61 |year=2000 |month=March |pmid=10725375 |pmc=16278 |doi=10.1073/pnas.050589597 |url=http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=10725375}}</ref> 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 [[Extracellular matrix|ECM]] proteins.


In the cortex and hippocampus, reelin is secreted by [[Cajal-Retzius cell]]s, Cajal cells, and Retzius cells during brain development.<!--
In the cortex and hippocampus, reelin is secreted by [[Cajal-Retzius cell]]s, Cajal cells, and Retzius cells during brain development.<!--


--><ref name="cr_cells">Meyer G, Goffinet AM, Fairen 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. PMID 10600995</ref><!--
--><ref name="cr_cells">{{cite journal |author=Meyer G, Goffinet AM, Fairén A |title=What is a Cajal-Retzius cell? A reassessment of a classical cell type based on recent observations in the developing neocortex |journal=Cereb. Cortex |volume=9 |issue=8 |pages=765–75 |year=1999 |month=December |pmid=10600995 |doi= |url=http://cercor.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10600995}}</ref><!--


--> In the cerebellum, Reelin is expressed first in the external [[granule cell]] layer (EGL) before the granule cell migration to the internal granule cell layer (IGL)<!--
--> In the cerebellum, Reelin is expressed first in the external [[granule cell]] layer (EGL) before the granule cell migration to the internal granule cell layer (IGL)<!--


--><ref>Schiffinann, S. N., Bernier, B. & Goffinet, A. M. (1997) Reelin mRNA expression during mouse brain development. Eur. J. Neurosci. 9, 1055-1071 PMID 9182958 </ref>.<!--
--><ref>{{cite journal |author=Schiffmann SN, Bernier B, Goffinet AM |title=Reelin mRNA expression during mouse brain development |journal=Eur. J. Neurosci. |volume=9 |issue=5 |pages=1055–71 |year=1997 |month=May |pmid=9182958 |doi= |url=}}</ref>.<!--


--> In the adult brain, Reelin is expressed by [[GABA]]-ergic [[interneuron]]s of the cortex and glutamatergic cerebellar neurons.<!--
--> In the adult brain, Reelin is expressed by [[GABA]]-ergic [[interneuron]]s of the cortex and glutamatergic cerebellar neurons.<!--


--><ref name="Interneurons">Pesold C, Impagnatiello F, Pisu MG, Uzunov DP, Costa E, Guidotti A, Caruncho HJ. (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. PMID 9501244</ref><!--
--><ref name="Interneurons">{{cite journal |author=Pesold C, Impagnatiello F, Pisu MG, ''et al'' |title=Reelin is preferentially expressed in neurons synthesizing gamma-aminobutyric acid in cortex and hippocampus of adult rats |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=95 |issue=6 |pages=3221–6 |year=1998 |month=March |pmid=9501244 |pmc=19723 |doi= |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=9501244}}</ref><!--


--> Among GABAergic interneurons, Reelin seems to be detected predominantly in those expressing [[calretinin]] and [[calbindin]], like [[bitufted neuron|bitufted]], [[horizontal neuron|horizontal]], and [[Martinotti cell]]s, but not [[parvalbumin]]-expressing cells, like [[chandelier neuron|chandelier]] or [[basket neuron]]s.<!--
--> Among GABAergic interneurons, Reelin seems to be detected predominantly in those expressing [[calretinin]] and [[calbindin]], like [[bitufted neuron|bitufted]], [[horizontal neuron|horizontal]], and [[Martinotti cell]]s, but not [[parvalbumin]]-expressing cells, like [[chandelier neuron|chandelier]] or [[basket neuron]]s.<!--


--><ref name="Regional_patterns_1998">Alcantara S, Ruiz M, D'Arcangelo G, Ezan F, de Lecea L, Curran T, Sotelo C, Soriano E. (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 [http://www.jneurosci.org/cgi/content/full/18/19/7779 free fulltext]</ref><!--
--><ref name="Regional_patterns_1998">{{cite journal |author=Alcántara S, Ruiz M, D'Arcangelo G, ''et al'' |title=Regional and cellular patterns of reelin mRNA expression in the forebrain of the developing and adult mouse |journal=J. Neurosci. |volume=18 |issue=19 |pages=7779–99 |year=1998 |month=October |pmid=9742148 |doi= |url=http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=9742148}}</ref><!--


--><!--
--><!--


--><ref name="No_parvalbumin_1999">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. PMID 10077664 [http://www.pnas.org/cgi/content/full/96/6/3217 free fulltext]</ref><!--
--><ref name="No_parvalbumin_1999">{{cite journal |author=Pesold C, Liu WS, Guidotti A, Costa E, Caruncho HJ |title=Cortical bitufted, horizontal, and Martinotti cells preferentially express and secrete reelin into perineuronal nets, nonsynaptically modulating gene expression |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=96 |issue=6 |pages=3217–22 |year=1999 |month=March |pmid=10077664 |pmc=15922 |doi= |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=10077664}}</ref><!--


--> Outside the brain, reelin is found in adult mammalian blood, [[liver]], pituitary [[pars intermedia]], and adrenal [[chromaffin cell]]s. <!--
--> Outside the brain, reelin is found in adult mammalian blood, [[liver]], pituitary [[pars intermedia]], and adrenal [[chromaffin cell]]s. <!--


--><ref name="bodyexpr">Smalheiser NR, Costa E, Guidotti A, Impagnatiello F, Auta J, Lacor P, Kriho V, Pappas GD. (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. PMID 10655522([http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=10655522 free full text])</ref><!--
--><ref name="bodyexpr">{{cite journal |author=Smalheiser NR, Costa E, Guidotti A, ''et al'' |title=Expression of reelin in adult mammalian blood, liver, pituitary pars intermedia, and adrenal chromaffin cells |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue=3 |pages=1281–6 |year=2000 |month=February |pmid=10655522 |pmc=15597 |doi= |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=10655522}}</ref><!--


--> In the liver, reelin is localized in [[hepatic stellate cell]]s.<ref name="liver2">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. PMID 15912522 [http://www3.interscience.wiley.com/cgi-bin/fulltext/110501225/HTMLSTART free full text]; [http://www3.interscience.wiley.com/cgi-bin/fulltext/110501225/PDFSTART full text PDF]</ref><!--
--> In the liver, reelin is localized in [[hepatic stellate cell]]s.<ref name="liver2">{{cite journal |author=Samama B, Boehm N |title=Reelin immunoreactivity in lymphatics and liver during development and adult life |journal=Anat Rec A Discov Mol Cell Evol Biol |volume=285 |issue=1 |pages=595–9 |year=2005 |month=July |pmid=15912522 |doi=10.1002/ar.a.20202 |url=http://www3.interscience.wiley.com/cgi-bin/fulltext/110501225/HTMLSTART}}</ref><!--


--> Its expression goes up when the liver is damaged, and returns to normal following its repair.<!--
--> Its expression goes up when the liver is damaged, and returns to normal following its repair.<!--


--> <ref name="Kobold_2002_liver1">Kobold D, Grundmann A, Piscaglia F, Eisenbach C, Neubauer K, Steffgen J, Ramadori G, Knittel T. (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. PMID 11983443</ref>
--> <ref name="Kobold_2002_liver1">{{cite journal |author=Kobold D, Grundmann A, Piscaglia F, ''et al'' |title=Expression of reelin in hepatic stellate cells and during hepatic tissue repair: a novel marker for the differentiation of HSC from other liver myofibroblasts |journal=J. Hepatol. |volume=36 |issue=5 |pages=607–13 |year=2002 |month=May |pmid=11983443 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0168827802000508}}</ref>


[[image:Schema of the Reelin protein vertical en.png|thumb|right|Schema of the Reelin protein]]
[[image:Schema of the Reelin protein vertical en.png|thumb|right|Schema of the Reelin protein]]

Revision as of 12:56, 7 July 2008

RELN
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesRELN, LIS2, PRO1598, RL, reelin, ETL7
External IDsOMIM: 600514; MGI: 103022; HomoloGene: 3699; GeneCards: RELN; OMA:RELN - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5649

19699

Ensembl

ENSG00000189056

ENSMUSG00000042453

UniProt

P78509

Q60841

RefSeq (mRNA)

NM_173054
NM_005045

NM_011261
NM_001310464

RefSeq (protein)

NP_005036
NP_774959

NP_001297393
NP_035391

Location (UCSC)Chr 7: 103.47 – 103.99 MbChr 5: 22.09 – 22.55 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Reelin is a protein found mainly in the brain, but also in the spinal cord, blood and other body organs and tissues. Reelin is crucial for regulating the processes of neuronal migration and positioning in the developing brain. Besides this important role in the early period, reelin continues to work in the adult brain. It modulates the synaptic plasticity by enhancing LTP induction and maintenance.[5][6] It also stimulates dendrite development[7] and regulates the continuing migration of neuroblasts generated in adult neurogenesis sites like subventricular and subgranular zones.

Reelin is implicated in pathogenesis of several brain diseases: significantly lowered expression of the protein have been found in schizophrenia and psychotic bipolar disorder. Total lack of reelin causes a form of lissencephaly; reelin also may play a role in Alzheimer's disease, temporal lobe epilepsy, and autism.

Reelin's name comes from the abnormal reeling gait of reeler mice,[8] which were found to have a deficiency of this brain protein and were homozygous for the RELN gene, which encodes reelin synthesis. The primary phenotype associated with loss of reelin function is inverted cortex, a neuroanatomical defect in which the six cortical layers are inverted. Heterozygous mice for the reelin gene have very little obvious neuroanatomical defect but those that they have resemble the changes of the human schizophrenic brain.


History

Normal and Reeler mice brain slices.

Mutant mice provide insight into the underlying molecular mechanisms of the development of the CNS. These 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 edition of Journal of Genetics by Douglas Scott Falconer.[8] Histopathological studies in the 1960's revealed that the reeler cerebellum is dramatically decreased in size and the normal laminar organization found in several brain regions is disrupted.[9] 1970's brought the discovery of cellular layers inversion in the mice neocortex[10], which attracted more attention to the reeler mutation.

In 1995, the RELN gene and protein were discovered at chromosome 7q22 by Gabriella D'Arcangelo and colleagues[11]. Almost immediately, Japanese scientists at Kochi Medical School had successfully created the first monoclonal antibody for reelin, called CR-50.[12] They noted that CR-50 reacted specifically with Cajal-Retzius neurons, whose functional role was unknown till then.

The downstream pathway of Reelin was clarified using other mutant mice, including yotari and scrambler. These mice 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, which encodes a homolog of Drosophila disabled, is the gene responsible for the phenotypes of these mutant mice, and Dab1 protein was absent (yotari) or only barely (scrambler) detectable in these mutants.[13] Targeted disruption of Dab1 also caused a phenotype similar to that of reeler.


wild-type mouse cortex
Reeler cortex

The Reelin receptors, apolipoprotein E receptor 2 and very-low-density lipoprotein receptor, were discovered serendipitously by Trommsdorff et al, who found that the double knockout mice for apolipoprotein E receptor 2 and very-low-density lipoprotein receptor, which they generated for another experiment, showed defects in cortical layering similar to that in reeler.[14]

In the July of 2006, a group of Japanese scientists published the first report of X-ray crystallography and electron tomography investigation of reelin structure.[15]

Secretion and localization of reelin

Studies show that Reelin is absent from synaptic vesicles and is secreted via constitutive secretory pathway, being stored in Golgi secretory vesicles.[16] 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.

In the cortex and hippocampus, reelin is secreted by Cajal-Retzius cells, Cajal cells, and Retzius cells during brain development.[17] In the cerebellum, Reelin is expressed first in the external granule cell layer (EGL) before the granule cell migration to the internal granule cell layer (IGL)[18]. In the adult brain, Reelin is expressed by GABA-ergic interneurons of the cortex and glutamatergic cerebellar neurons.[19] 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.[20][21] Outside the brain, reelin is found in adult mammalian blood, liver, pituitary pars intermedia, and adrenal chromaffin cells. [22] In the liver, reelin is localized in hepatic stellate cells.[23] Its expression goes up when the liver is damaged, and returns to normal following its repair. [24]

Schema of the Reelin protein

Structure

Reelin is a secreted extracellular matrix glycoprotein composed of 3461 amino acids with a relative molecular mass of 388 kDa.

Reelin molecule starts with a signaling peptide 27 amino acids in length, followed by a region bearing similarity to F-spondin, marked as "SP" on the scheme, and by a region unique to reelin, marked as "H". Next come the 8 repeats of 300-350 amino acids. These are called reelin repeats and have an EGF motif at their center, dividing each repeat into two subrepeats, A and B. Despite this interruption, the two subdomains make direct contact, resulting in a compact overall structure.[15]

The last comes a highly basic and short C-terminal region (CTR, marked "+") with a length of 32 amino acids. This region is extremely conservative, being 100% identical in all investigated mammals. It was thought that CTR is necessary for reelin secretion, because Orleans reeler mutation, which lacks a part of 8th repeat and the whole CTR, is unable to secrete the misshaped protein, leading to its concentration in cytoplasm. However, one recent study has shown that the CTR is not essential for secretion, which is most probably hindered then reelin is cut along one of the repeats.[25]

Reelin is cleaved in vivo at two sites located after domains 2 and 6 - approximately between repeats 2 and 3 and between repeats 6 and 7, resulting in the production of three fragments.[26] This splitting does not decrease the protein's activity, as constructs made of the predicted central fragments (repeats 3–6) bind to lipoprotein receptors, trigger Dab1 phosphorylation and mimic functions of reelin during cortical plate development.[27]

Function and mechanism of action

In the process of neural development, Reelin acts on migrating neuronal precursors and controls correct cell positioning in the cortex and other brain structures. The proposed role is one of a dissociation signal for neuronal groups, allowing them to separate and go from tangential chain-migration to radial individual migration.[28] Dissociation detaches migrating neurons from the glial cells that are acting as their guides, converting them into individual cells that can strike out alone to find their final position.

In the adult brain, Reelin plays an important role by modulating cortical pyramidal neuron dendritic spine expression density, the branching of dendrites, and the expression of long-term potentiation.

Mechanism of action

Reelin acts on two receptors:

  • VLDLR (very-low-density lipoprotein receptor) and the
  • ApoER2 (apolipoprotein E receptor 2),

which are members of the Low density lipoprotein receptor gene family.

The intracellular adaptor DAB1 binds to the VLDLR and ApoER2 through an NPxY motif and is involved in transmission of Reelin signals through these lipoprotein receptors.

The proposal that the protocadherin CNR1 behaves as a Reelin receptor[29] has been disproved.[27]

It has been shown that alpha-3-beta-1 integrin binds to the N-terminal region of reelin, a site distinct from the region of reelin shown to associate with other reelin receptors such as VLDLR/ApoER2.[30]

Reelin molecules have been shown[31] [32] to form a large protein complex, a disulfide-linked homodimer. If the homodimer fails to form, efficient tyrosine phosphorylation of DAB1 also fails.

Reelin-dependent strengthening of long-term potentiation is caused by ApoER2 interaction with NMDA receptor. This interaction happens when ApoER2 has a region coded by exon 19. ApoER2 gene is alternatively spliced, with the exon 19-containing variant more actively produced during periods of activity.[33]

Role in brain pathology

Lissencephaly

Disruptions of the RELN gene are condsidered to be the cause of the rare form of lissencephaly with cerebellar hypoplasia called Norman-Roberts syndrome.[34][35] The mutations disrupt splicing of RELN cDNA, resulting in low or undetectable amounts of reelin protein. The phenotype in these patients was characterized by hypotonia, ataxia, and developmental delay, with lack of unsupported sitting and profound mental retardation with little or no language development. Seizures and congenital lymphedema were also present.

Schizophrenia

Reduced expression of reelin and its mRNA levels in the brains of schizophrenia sufferers had been reported in 1998[36] and 2000[37] and independently confirmed in the postmortem studies of hippocampus samples[38] and in the cortex studies.[39][40] The reduction may reach up to 50% in some brain regions and is coupled with reduced expression of GAD-67 enzyme,[41] which catalyses the transition of glutamate to GABA. Blood levels of reelin and its isoforms are also altered in schizophrenia, along with other mood disorders, according to one study.[42] Reduced reelin mRNA prefrontal expression in schizophrenia was found to be the most statistically relevant disturbance found in the multicenter study conducted in 14 separate laboratories in 2001 by Stanley Foundation Neuropathology Consortium.[43]

Epigenetic hypermethylation of DNA in schizophrenia patients is proposed as a cause of the reduction,[44][45] in accordance with the knowledge that administration of methionine to schizophrenic patients results in a profound exacerbation of schizophrenia symptoms in sixty to seventy percent of patients, a fact discovered in the 1960's.[46][47][48][49] In contrast with initial data, subsequent studies failed to confirm the hypermethylation.[50][51] A postmortem study comparing DNMT1 and Reelin mRNA expression in cortical layers I and V of schizophrenic patients and normal controls demonstrated that in the layer V both DNMT1 and Reelin levels were normal, while in the layer I DNMT1 was threefold higher, probably leading to the twofold decrease in the Reelin expression. [52] Methylation inhibitors and histone deacetylase inhibitors, such as valproic acid, increase reelin mRNA levels,[53] [54] [55] while L-methionine treatment downregulates the phenotypic expression of reelin. [56]

Heterozygous reeler mouse, which is haploinsufficient for the reeler gene, shares several neurochemical and behavioral abnormalities with schizophrenia and bipolar disorder[57], but considered as not suitable for use as a genetic mouse model of schizophrenia.[58]

Bipolar disorder

Decrease in RELN expression is typical of bipolar disorder with psychosis, but is not characteristic of patients with major depression without psychosis.[37]

Autism

A number of studies have shown an association between the reelin gene and autism[59] [60]. A couple of studies were unable to duplicate linkage findings, however.[61][62]

Temporal Lobe Epilepsy

Decreased reelin expression in the hippocampal tissue samples from patients with temporal lobe epilepsy was found to be directly correlated to the extent of granule cell dispersion, a major feature of the disease.[63] [64] According to one study, prolonged seizures in a rat model of mesial temporal lobe epilepsy have led to the loss of reelin-expressing interneurons and subsequent ectopic chain migration and aberrant integration of newborn dentate granule cells. Without reelin, the chain-migrating neuroblasts failed to detach properly.[65]

Alzheimer's disease

According to one study, reelin expression and glycosylation patterns are altered in Alzheimer's disease. In the cortex of the patients, reelin levels were 40% higher compared with controls, but the cerebellar levels of the protein remain normal in the same patients.[66] This finding correlates with an earlier study showing the presence of Reelin associated with amyloid plaques in a transgenic AD mouse model. [67]

  1. Forster E, Jossin Y, Zhao S, Chai X, Frotscher M, Goffinet AM. (2006) Recent progress in understanding the role of Reelin in radial neuronal migration, with specific emphasis on the dentate gyrus. Eur J Neurosci. 23(4):901-9. Review. PMID 16519655 (free full text)

Articles, publications, webpages

Figures and images

References

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