Editing Reelin

{{short description|Large secreted extracellular matrix glycoprotein involved in neuronal migration}}
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{{Use dmy dates|date=April 2024}}
{{Infobox_gene}}
'''Reelin''', encoded by the '''''RELN''''' gene,<ref>{{Cite web|title = RELN gene|url = http://ghr.nlm.nih.gov/gene/RELN|website = Genetics Home Reference|date = 1 August 2013|access-date = 11 September 2022}}</ref> is a large secreted [[extracellular matrix]] [[glycoprotein]] that helps regulate processes of [[neuronal migration]] and positioning in the developing brain by controlling [[cell–cell interactions]]. Besides this important role in early [[Developmental biology|development]], reelin continues to work in the adult brain.<ref>{{cite journal | vauthors = Bosch C, Muhaisen A, Pujadas L, Soriano E, Martínez A | title = Reelin Exerts Structural, Biochemical and Transcriptional Regulation Over Presynaptic and Postsynaptic Elements in the Adult Hippocampus | journal = Frontiers in Cellular Neuroscience | volume = 10 | pages = 138 | date = 2016 | pmid = 27303269 | pmc = 4884741 | doi = 10.3389/fncel.2016.00138 | doi-access = free }}</ref> It modulates [[synaptic plasticity]] by enhancing the induction and maintenance of [[long-term potentiation]].<ref name="LTP1" /><ref name="LTP2" /> It also stimulates dendrite and [[dendritic spine]] development in the [[hippocampus]],<ref name="Niu_2004" /><ref name="pmid18842893" /> and regulates the continuing migration of [[neuroblast]]s generated in [[adult neurogenesis]] sites of the [[subventricular zone|subventricular]] and [[subgranular zone]]s. It is found not only in the [[brain]] but also in the [[liver]], [[Thyroid|thyroid gland]], [[adrenal gland]], [[fallopian tube]], [[breast]] and in comparatively lower levels across a range of anatomical regions.<ref name=":0">{{Cite web|url=https://www.proteinatlas.org/ENSG00000189056-RELN/tissue|title=Tissue expression of RELN - Summary - The Human Protein Atlas|website=www.proteinatlas.org|access-date=28 May 2018}}</ref>

Reelin has been suggested to be implicated in pathogenesis of several brain diseases. The expression of the protein has been found to be significantly lower in [[schizophrenia]] and psychotic [[bipolar disorder]],<ref name="szconfirm1" /> but the cause of this observation remains uncertain, as studies show that [[Reelin#Psychotropic medication|psychotropic medication itself affects reelin expression]]. Moreover, [[Epigenetics|epigenetic]] hypotheses aimed at explaining the changed levels of reelin expression<ref name="Schizophrenia Research Forum: Current Hypotheses" /> are controversial.<ref name="pmid17870056" /><ref name="pmid18319075" /> Total lack of reelin causes a form of [[lissencephaly]]. Reelin may also play a role in [[Alzheimer's disease]],<ref>{{cite journal | vauthors = Kovács KA | title = Relevance of a Novel Circuit-Level Model of Episodic Memories to Alzheimer's Disease | journal = International Journal of Molecular Sciences | volume = 23 | issue = 1 | pages = 462 | date = December 2021 | doi = 10.3390/ijms23010462 | pmid = 35008886 | pmc = 8745479 | doi-access = free }}</ref> [[temporal lobe epilepsy]] and [[autism]].

Reelin's name comes from the abnormal reeling [[gait]] of ''[[reeler]]'' mice,<ref name="falconer" /> which were later found to have a deficiency of this brain [[protein]] and were [[Zygosity|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 [[central nervous system]] (CNS). The mice [[Zygosity|heterozygous]] for the reelin gene, while having little neuroanatomical defects, display the [[endophenotype|endophenotypic]] traits linked to psychotic disorders.<ref name="pmid16769115" />

== Discovery ==
[[File:Reeler 100kbps.ogv|230px|thumb|left|Video: the reeler mice mutants, first described in 1951 by [[D.S.Falconer]], were later found to lack reelin protein.]]

[[File:Reeler lamination.png|thumb|250px|Normal and [[reeler]] mice brain slices.]]
Mutant mice have provided insight into the underlying molecular mechanisms of the development of the [[central nervous system]]. Useful spontaneous mutations were first identified by scientists who were 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.{{citation needed|date=January 2016}}

The "[[reeler]]" mouse was described for the first time in 1951 by [[Douglas Scott Falconer|D.S.Falconer]] in [[Edinburgh University]] as a spontaneous variant arising in a colony of at least mildly inbred snowy-white bellied mice stock in 1948.<ref name="falconer" /> [[Histopathology|Histopathological]] studies in the 1960s revealed that the [[cerebellum]] of reeler mice is dramatically decreased in size while the normal laminar organization found in several brain regions is disrupted.<ref name="hamburgh" /> The 1970s brought about the discovery of cellular layer inversion in the mouse neocortex,<ref name="caviness" /> which attracted more attention to the reeler mutation.

In 1994, a new [[allele]] of reeler was obtained by means of insertional [[mutagenesis]].<ref name="pmid7972007" /> This provided the first [[molecular marker]] of the [[Locus (genetics)|locus]], permitting the RELN gene to be mapped to chromosome 7q22 and subsequently cloned and identified.<ref name="Darcan1" /> 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 antibodies]] for reelin, and were termed CR-50 (Cajal-Retzius marker 50).<ref name="cr50" /> They noted that CR-50 reacted specifically with [[Cajal-Retzius cell|Cajal-Retzius neurons]], whose functional role was unknown until then.{{citation needed|date=January 2016}}

The Reelin receptors, [[ApoER2|apolipoprotein E receptor 2]] (ApoER2) and [[VLDLR|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.<ref name="pmid9837937" /> They then went on to show that the double [[Gene knockout|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.--><ref name="receptors_discovery" />

The [[Upstream and downstream (transduction)|downstream]] [[neural pathway|pathway]] of reelin was further clarified with the help of other mutant mice, including [[yotari]] and [[Scrambler mouse|scrambler]]. These mutants have phenotypes similar to that of reeler mice, but without mutation in reelin. It was then demonstrated that the mouse ''disabled homologue 1'' ([[DAB1|Dab1]]) gene is responsible for the phenotypes of these mutant mice, as Dab1 protein was absent (yotari) or only barely detectable (scrambler) in these mutants.<ref name="yotari_and_scrambler" /> 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.{{citation needed|date=January 2016}}

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.<ref name="reelin_G_scholar_search_title" /><ref name="Reelin_book_2008" />

== Tissue distribution and secretion ==
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" /> 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]] proteins.{{citation needed|date=January 2016}}

During the brain development, reelin is secreted in the cortex and hippocampus by the so-called [[Cajal-Retzius cell]]s, Cajal cells, and Retzius cells.<ref name="cr_cells" /> 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,<ref name="pmid9671277" /> 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) takes place.<ref name="Schiffmann" />

Having peaked just after the birth, the synthesis of reelin subsequently goes down sharply, becoming more diffuse compared with the distinctly laminar expression in the developing brain. In the adult brain, reelin is expressed by [[GABA]]-ergic [[interneuron]]s of the cortex and glutamatergic cerebellar neurons,<ref name="Interneurons" /> the glutamatergic stellate cells and fan cells in the superficial [[entorhinal cortex]] that are supposed to carry a role in encoding new [[episodic memories]],<ref>{{cite journal | vauthors = Kovács KA | title = Episodic Memories: How do the Hippocampus and the Entorhinal Ring Attractors Cooperate to Create Them? | journal = Frontiers in Systems Neuroscience | volume = 14 | pages = 68 | date = September 2020 | doi = 10.3389/fnsys.2020.559186 | pmid = 33013334 | pmc = 7511719 | doi-access = free }}</ref> 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 neuron|bitufted]], [[horizontal neurons|horizontal]], and [[Martinotti cell]]s, but not [[parvalbumin]]-expressing cells, like [[chandelier cell|chandelier]] or [[basket neuron]]s.<ref name="Regional_patterns_1998" /><ref name="No_parvalbumin_1999" /> In the white matter, a minute proportion of [[interstitial neuron]]s has also been found to stain positive for reelin expression.<ref name="pmid19543540" />

[[File:Schema of the Reelin protein vertical en.png|thumb|Schema of the reelin protein]]
Outside the brain, reelin is found in adult mammalian blood, [[liver]], pituitary [[pars intermedia]], and adrenal [[chromaffin cell]]s.<ref name="bodyexpr" /> In the liver, reelin is localized in [[hepatic stellate cell]]s.<ref name="liver2" /> The expression of reelin increases when the liver is damaged, and returns to normal following its repair.<ref name="Kobold_2002_liver1" />
In the eyes, reelin is secreted by [[retinal ganglion cell]]s and is also found in the [[Corneal endothelium|endothelial layer of the cornea]].<ref name="pmid17120005" /> Just as in the liver, its expression increases after an injury has taken place.{{citation needed|date=January 2016}}

The protein is also produced by the [[odontoblast]]s, which are cells at the margins of the dental pulp. Reelin is found here both during odontogenesis and in the mature tooth.<ref name="pmid10980418" /> Some authors suggest that odontoblasts play an additional role as sensory cells able to [[Transduction (physiology)|transduce]] pain signals to the nerve endings.<ref name="pmid16831873" /> According to the hypothesis, reelin participates in the process<ref name="Reelin_book_2008" /> by enhancing the contact between odontoblasts and the nerve terminals.<ref name="pmid15464360" />

== Structure ==
[[File:2e26.png|thumb|left|250px|The structure of two [[mouse|murine]] ''reelin repeats'' as revealed by [[X-ray crystallography]].<ref name="pmid17548821" />]]
Reelin is composed of 3461 amino acids with a relative molecular mass of 388 [[Atomic mass unit|kDa]]. It also has [[serine protease]] activity.<ref name="pmid11689558" /> Murine RELN gene consists of 65 [[exon]]s spanning approximately 450 [[base pair|kb]].<ref name="pmid9417911" /> One exon, coding for only two amino acids near the protein's [[C-terminus]], undergoes [[alternative splicing]], but the exact functional impact of this is unknown.<ref name="Reelin_book_2008" /> Two transcription initiation sites and two polyadenylation sites are identified in the gene structure.<ref name="pmid9417911" />

The reelin protein starts with a signaling peptide 27 amino acids in length, followed by a region bearing similarity to [[spondin 1|F-spondin]] (the [[reeler domain]]), marked as "SP" on the scheme, and by a region unique to reelin, marked as "H". Next comes 8 repeats of 300–350 amino acids. These are called ''reelin repeats'' and have an [[epidermal growth factor]] motif at their center, dividing each repeat into two subrepeats, ''A'' (the [[BNR/Asp-box repeat]]) and ''B'' (the [[EGF-like domain]]). Despite this interruption, the two subdomains make direct contact, resulting in a compact overall structure.<ref name="reelinstructure2006japan" />

The final reelin domain contains a highly basic and short C-terminal region (CTR, marked "+") with a length of 32 amino acids. This region is highly conserved, being 100% identical in all investigated mammals. It was thought that CTR is necessary for reelin secretion, because the 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, other studies have shown that the CTR is not essential for secretion itself, but mutants lacking the CTR were much less efficient in activating downstream signaling events.<ref name="Nakano_2007_CTR_1" />

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.<ref name="cleave" /> 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|Dab1]] [[phosphorylation]] and mimic functions of reelin during [[cortical plate]] development.<ref name="centralfragment" /> Moreover, the processing of reelin by embryonic neurons may be necessary for proper corticogenesis.<ref name="pmid17442808" />

== Function ==
[[File:Rostral migratory stream mouse cropped.jpg|thumb|280px|As they travel through the [[rostral migratory stream]], neuroblasts are held together, probably in part by [[thrombospondin-1]]'s binding to the reelin receptors [[ApoER2]] and [[VLDLR]].<ref name="pmid18946489" /> As they arrive to the destination, the groups are dispersed by reelin and cells strike out on their individual paths. A fragment of an [[:Commons:Image:Rostral migratory stream mouse.jpg|illustration]] from Lennington et al., 2003.<ref name="pmid14614786" />]]
The primary functions of Reelin are the regulation of corticogenesis and neuronal cell positioning in the prenatal period, but the protein also continues to play a role in adults. Reelin is found in numerous tissues and organs, and one could roughly subdivide its functional roles by the time of expression and by localisation of its action.<ref name=":0" />

=== During development ===
A number of non-nervous tissues and organs express reelin during development, with the expression sharply going down after organs have been formed. The role of the protein here is largely unexplored, because the knockout mice show no major pathology in these organs. Reelin's role in the growing central nervous system has been extensively characterized. It promotes the differentiation of progenitor cells into [[radial glia]] and affects the orientation of its fibers, which serve as the guides for the migrating neuroblasts.<ref name="pmid12925587" /> The position of reelin-secreting cell layer is important, because the fibers orient themselves in the direction of its higher concentration.<ref name="pmid18197264" /> For example, reelin regulates the development of layer-specific connections in hippocampus and entorhinal cortex.<ref name="DerRio1997" /><ref name="Borrell1999" />

[[File:Reelin controls directed growth of radial fibers - journal.pone.0001454.g005 center cropped.jpg|thumb|280px|Reelin controls the direction of radial glia growth. A fragment of an [[Commons:Image:Journal.pone.0001454.g005.jpg|illustration]] from Nomura T. et al., 2008.<ref name="pmid18197264" /> Reelin-expressing cells (red) on C stimulate the growth of green glial fibers, while on B, where the red cells do not express reelin, radial glia is more disarrayed.]]

Mammalian [[corticogenesis]] is another process where reelin plays a major role. In this process the temporary layer called preplate is split into the marginal zone on the top and subplate below, and the space between them is populated by neuronal layers in the inside-out pattern. Such an arrangement, where the newly created neurons pass through the settled layers and position themselves one step above, is a distinguishing feature of mammalian brain, in contrast to the evolutionary older reptile cortex, in which layers are positioned in an "outside-in" fashion. When reelin is absent, like in the mutant [[reeler]] mouse, the order of cortical layering becomes roughly inverted, with younger neurons finding themselves to be unable to pass the settled layers. Subplate neurons fail to stop and invade the upper most layer, creating the so-called superplate in which they mix with [[Cajal-Retzius cell]]s and some cells normally destined for the second layer.{{citation needed|date=January 2016}}

[[File:An increase of Reelin-positive cells changes morphology of migrating neurons - journal.pone.0001454.g007.jpg|thumb|280px|Increased reelin expression changes the morphology of migrating neurons: unlike the round neurons with short branches (C) they assume bipolar shape (D) and attach themselves (E) to the [[radial glia]] fibers that are extending in the direction of reelin-expressing cells. Nomura T. et al., 2008.<ref name="pmid18197264" />]]

There is no agreement concerning the role of reelin in the proper positioning of cortical layers. The original hypothesis, that the protein is a stop signal for the migrating cells, is supported by its ability to induce the dissociation,<ref name="roleofreelin1" /> its role in asserting the compact granule cell layer in the hippocampus, and by the fact that migrating neuroblasts evade the reelin-rich areas. But an experiment in which murine corticogenesis went normally despite the malpositioned reelin secreting layer,<ref name="pmid16410414" /> and lack of evidence that reelin affects the growth cones and leading edges of neurons, caused some additional hypotheses to be proposed. According to one of them, reelin makes the cells more susceptible to some yet undescribed positional signaling cascade.{{citation needed|date=June 2013}}

Reelin may also ensure correct neuronal positioning in the [[spinal cord]]: according to one study, location and level of its expression affects the movement of sympathetic preganglionic neurons.<ref name="pmid19412957" />

The protein is thought to act on migrating neuronal precursors and thus 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.<ref name="roleofreelin1" /> Dissociation detaches migrating neurons from the [[glial cell]]s that are acting as their guides, converting them into individual cells that can strike out alone to find their final position.{{citation needed|date=January 2016}}

[[File:Profile of intense and punctate reelin IR during hippocampal maturation journal pone 0005505 g001 cr.png|thumb|280px|Top: Representative image of somatic reelin immunoreactivities found in 12-day-in-vitro hippocampal neurons. Bottom: reelin immunofluorescence (red) overlaid with [[MAP2]] [[counterstain]] (green). A fragment of an [[Commons:Image:Profile of intense and punctate reelin IR during hippocampal maturation journal pone 0005505 g001.png|illustration]] from Campo et al., 2009.<ref name="pmid19430527" />]]

Reelin takes part in the developmental change of [[NMDA receptor]] configuration, increasing mobility of [[NR2B]]-containing receptors and thus decreasing the time they spend at the [[synapse]].<ref name="OlivierManzoni" />{{Dead link|date=December 2011}}<ref name="pmid15987942" /><ref name="pmid17881522" /> It has been hypothesized that this may be a part of the mechanism behind the "NR2B-NR2A switch" that is observed in the brain during its postnatal development.<ref name="pmid15470155" /> Ongoing reelin secretion by GABAergic hippocampal neurons is necessary to keep NR2B-containing NMDA receptors at a low level.<ref name="pmid19430527" />

=== In adults ===
{{Further|Adult neurogenesis}}
In the adult nervous system, reelin plays an eminent role at the two most active neurogenesis sites, the subventricular zone and the dentate gyrus. In some species, the neuroblasts from the subventricular zone migrate in chains in the [[rostral migratory stream]] (RMS) to reach the olfactory bulb, where reelin dissociates them into individual cells that are able to migrate further individually. They change their mode of migration from tangential to radial, and begin using the radial glia fibers as their guides. There are studies showing that along the RMS itself the two receptors, [[ApoER2]] and [[VLDLR]], and their intracellular adapter [[DAB1]] function independently of Reelin,<ref name="pmid17494763" /> most likely by the influence of a newly proposed ligand, [[thrombospondin-1]].<ref name="pmid18946489" /> In the adult dentate gyrus, reelin provides guidance cues for new neurons that are constantly arriving to the granule cell layer from subgranular zone, keeping the layer compact.<ref name="dentate_gyrus" />

Reelin also plays an important role in the adult brain by modulating cortical pyramidal neuron [[dendritic spine]] expression density, the branching of [[dendrite]]s, and the expression of [[long-term potentiation]]<ref name="LTP2" /> as its secretion is continued diffusely by the GABAergic cortical interneurons those origin is traced to the medial [[ganglionic eminence]].

In the adult organism the non-neural expression is much less widespread, but goes up sharply when some organs are injured.<ref name="Kobold_2002_liver1" /><ref name="pmid17120005" /> The exact function of reelin upregulation following an injury is still being researched.{{citation needed|date=January 2016}}

==Evolutionary significance==
[[File:Cajal-Retzius cell drawing by Cajal 1891.gif|left|thumb|440px|[[Cajal-Retzius cell]]s, as drawn by Cajal in 1891. The development of a distinct layer of these reelin-secreting cells played a major role in brain evolution.]]
[[File:Schematic illustration of differences in neuronal specification and migration patterns between the mammalian and avian pallium.png|thumb|left|250px|Neuronal development: mammals (left) and avians (right) have different patterns of reelin expression (pink). Nomura T. et al., 2008.<ref name="pmid18197264" />]]
Reelin-DAB1 interactions could have played a key role in the structural evolution of the cortex that evolved from a single layer in the common predecessor of the [[amniote]]s into multiple-layered cortex of contemporary mammals.<ref name="pmid11137154" /> Research shows that reelin expression goes up as the cortex becomes more complex, reaching the maximum in the human brain in which the reelin-secreting Cajal-Retzius cells have significantly more complex axonal arbour.<ref name="pmid16519657" /> Reelin is present in the telencephalon of all the vertebrates studied so far, but the pattern of expression differs widely. For example, [[zebrafish]] have no Cajal-Retzius cells at all; instead, the protein is being secreted by other neurons.<ref name="pmid11173219" /><ref name="pmid12124768" /> These cells do not form a dedicated layer in amphibians, and radial migration in their brains is very weak.<ref name="pmid11173219" />

As the cortex becomes more complex and convoluted, migration along the radial glia fibers becomes more important for the proper lamination. The emergence of a distinct reelin-secreting layer is thought to play an important role in this evolution.<ref name="pmid18197264" /> There are conflicting data concerning the importance of this layer,<ref name="pmid16410414" /> and these are explained in the literature either by the existence of an additional signaling positional mechanism that interacts with the reelin cascade,<ref name="pmid16410414" /> or by the assumption that mice that are used in such experiments have redundant secretion of reelin<ref name="pmid17132178" /> compared with more localized synthesis in the human brain.<ref name="pmid9671277" />

Cajal-Retzius cells, most of which disappear around the time of birth, coexpress reelin with the [[HAR1]] gene that is thought to have undergone the most significant evolutionary change in humans compared with chimpanzee, being the most "evolutionary accelerated" of the genes from the [[human accelerated regions]].<ref name="pmid16915236" /> There is also evidence of that variants in the DAB1 gene have been included in a recent selective sweep in Chinese populations.<ref name="pmid17542651" /><ref name="NYT1" />

==Mechanism of action==
[[File:Model of Reelin and Lis1 signaling - journal.pone.0000252.g008.png|thumb|280px|The main reelin signaling cascade (ApoER2 and VLDLR) and its interaction with [[LIS1]]. Zhang et al., 2008<ref name="Zhang_2007_Pafah1b" /><br /> '''SFK''': [[Src Family Kinases|Src family kinases]].<br />'''JIP''': [[MAPK8IP1|JNK-interacting protein 1]]]]

=== Receptors ===
Reelin's control of cell-cell interactions is thought to be mediated by binding of reelin to the two members of [[low density lipoprotein receptor gene family]]: [[VLDL receptor|VLDLR]] and the [[low density lipoprotein receptor-related protein 8|ApoER2]].<ref name="pmid10571240" /><ref name="pmid10571241" /><ref name="pmid12899622" /><ref name="pmid12670700" /> The two main reelin receptors seem to have slightly different roles: VLDLR conducts the stop signal, while ApoER2 is essential for the migration of late-born neocortical neurons.<ref name="pmid17913789" /> It also has been shown that the N-terminal region of reelin, a site distinct from the region of reelin shown to associate with VLDLR/ApoER2 binds to the alpha-3-beta-1 [[integrin]] receptor.<ref name="integrin" /> The proposal that the proto[[cadherin]] CNR1 behaves as a Reelin receptor<ref name="cadherin" /> has been disproven.<ref name="centralfragment" />

As members of lipoprotein receptor superfamily, both VLDLR and ApoER2 have in their structure an internalization domain called [[NPxY]] [[Structural motif|motif]]. After binding to the receptors reelin is internalized by [[endocytosis]], and the N-terminal fragment of the protein is re-secreted.<ref name="pmid19303411" /> This fragment may serve postnatally to prevent apical dendrites of cortical layer II/III pyramidal neurons from overgrowth, acting via a pathway independent of canonical reelin receptors.<ref name="pmid19366679" />

Reelin receptors are present on both [[neuron]]s and [[glial cell]]s. Furthermore, [[radial glia]] express the same amount of [[Low density lipoprotein receptor-related protein 8|ApoER2]] but being ten times less rich in [[VLDL receptor|VLDLR]].<ref name="pmid12925587" /> [[CD29|beta-1 integrin receptors]] on glial cells play more important role in neuronal layering than the same receptors on the migrating neuroblasts.<ref name="pmid18077697" />

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.<ref name="Reelin_ApoER2_Exon19_2005_Beffert" /> According to one study, the hippocampal reelin expression rapidly goes up when there is need to store a memory, as [[demethylase]]s open up the RELN gene.<ref name="pmid17359920" /> The activation of dendrite growth by reelin is apparently conducted through [[Src (gene)|Src]] family [[kinase]]s and is dependent upon the expression of [[CRK (gene)|Crk]] family proteins,<ref name="pmid18477607" /> consistent with the interaction of Crk and CrkL with tyrosine-phosphorylated Dab1.<ref name="pmid15062102" /> Moreover, a [[Cre-Lox recombination|Cre-loxP recombination]] mouse model that lacks [[CRK (gene)|Crk]] and [[CRKL|CrkL]] in most neurons<ref name="pmid19074029" /> was reported to have the [[reeler]] phenotype, indicating that Crk/CrkL lie between [[DAB1]] and [[AKT1|Akt]] in the reelin signaling chain.

=== Signaling cascades ===
Reelin activates the signaling cascade of [[NOTCH1|Notch-1]], inducing the expression of [[FABP7]] and prompting progenitor cells to assume [[radial glia]]l phenotype.<ref name="pmid18593473" /> In addition, corticogenesis ''in vivo'' is highly dependent upon reelin being processed by embryonic neurons,<ref name="pmid17442808" /> which are thought to secrete some as yet unidentified [[metalloproteinase]]s that free the central signal-competent part of the protein. Some other unknown proteolytic mechanisms may also play a role.<ref name="pmid12959647" /> It is supposed that full-sized reelin sticks to the extracellular matrix fibers on the higher levels, and the central fragments, as they are being freed up by the breaking up of reelin, are able to permeate into the lower levels.<ref name="pmid17442808" /> It is possible that as [[neuroblast]]s reach the higher levels they stop their migration either because of the heightened combined expression of all forms of reelin, or due to the peculiar mode of action of the full-sized reelin molecules and its homodimers.<ref name="Reelin_book_2008" />

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. It becomes phosphorylated by [[Src (gene)|Src]]<ref name="pmid9009273" /> and [[FYN|Fyn]]<ref name="pmid12526739" /> kinases and apparently stimulates the [[actin]] cytoskeleton to change its shape, affecting the proportion of integrin receptors on the cell surface, which leads to the change in [[Cell adhesion|adhesion]]. Phosphorylation of DAB1 leads to its [[ubiquitination]] and subsequent degradation, and this explains the heightened levels of DAB1 in the absence of reelin.<ref name="pmid17974915" /> Such [[negative feedback]] is thought to be important for proper cortical lamination.<ref name="pmid18006681" /> Activated by two antibodies, VLDLR and ApoER2 cause DAB1 phosphorylation but seemingly without the subsequent degradation and without rescuing the [[reeler]] phenotype, and this may indicate that a part of the signal is conducted independently of DAB1.<ref name="centralfragment" />

[[File:Reelin induces GFAP and FABP7 via Notch1.jpg|thumb|280px|Reelin stimulates the progenitor cells to differentiate into radial glia, inducing the expression of radial glial marker [[FABP7|BLBP]] by affecting the [[NOTCH1]] cascade. A fragment of an [[Commons:Image:Reelin-induced radial glial phenotype is dependent on gamma-secretase activity.jpg|illustration]] from Keilani et al., 2008.<ref name="pmid18593473" />]]

A protein having an important role in [[lissencephaly]] and accordingly called [[LIS1]] ([[PAFAH1B1]]), was shown to interact with the intracellular segment of VLDLR, thus reacting to the activation of reelin pathway.<ref name="Zhang_2007_Pafah1b" />

=== Complexes ===
Reelin molecules have been shown<ref name="hugecomplex" /><ref name="complex" /> to form a large protein complex, a [[disulfide bond|disulfide-linked]] [[homodimer]]. If the homodimer fails to form, efficient tyrosine [[phosphorylation]] of DAB1 ''in vitro'' fails. Moreover, the two main receptors of reelin are able to form clusters<ref name="pmid14729980" /> that most probably play a major role in the signaling, causing the intracellular adaptor DAB1 to dimerize or oligomerize in its turn. Such clustering has been shown in the study to activate the signaling chain even in the absence of Reelin itself.<ref name="pmid14729980" /> In addition, reelin itself can cut the peptide bonds holding other proteins together, being a [[serine protease]],<ref name="pmid11689558" /> and this may affect the cellular adhesion and migration processes. Reelin signaling leads to phosphorylation of [[actin]]-interacting protein [[cofilin 1]] at ser3; this may stabilize the actin cytoskeleton and anchor the leading processes of migrating neuroblasts, preventing their further growth.<ref name="pmid19129405" /><ref name="pmid19396394" />

=== Interaction with Cdk5 ===
[[Cyclin-dependent kinase 5]] (Cdk5), a major regulator of neuronal migration and positioning, is known to phosphorylate [[DAB1]]<ref name="pmid14645539" /><ref name="pmid16529723" /><ref name="pmid12077184" /> and other cytosolic targets of reelin signaling, such as [[Tau protein|Tau]],<ref name="pmid8253190" /> which could be activated also via reelin-induced deactivation of [[GSK3B]],<ref name="pmid12376533" /> and [[NDEL1|NUDEL]],<ref name="pmid11163259" /> associated with [[PAFAH1B1|Lis1]], one of the DAB1 targets. [[Long-term potentiation|LTP]] induction by reelin in hippocampal slices fails in [[CDK5R1|p35]] knockouts.<ref name="pmid14985430" /> P35 is a key Cdk5 activator, and double p35/Dab1, p35/RELN, p35/ApoER2, p35/VLDLR knockouts display increased neuronal migration deficits,<ref name="pmid14985430" /><ref name="pmid11226314" /> indicating a synergistic action of reelin → ApoER2/VLDLR → DAB1 and p35/p39 → Cdk5 pathways in the normal corticogenesis.

== Possible pathological role ==

=== Lissencephaly ===
Disruptions of the RELN gene are considered to be the cause of the rare form of [[lissencephaly]] with [[cerebellar hypoplasia]] classed as a [[microlissencephaly]] called [[Norman-Roberts syndrome]].<ref name="liss2000" /><ref name="liss2001" /> The mutations disrupt [[Splicing (genetics)|splicing]] of the RELN [[Messenger RNA|mRNA]] transcript, 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]] are also present. A novel [[chromosomal translocation]] causing the syndrome was described in 2007.<ref name="pmid17431900" />

=== Schizophrenia ===
Reduced expression of reelin and its [[Messenger RNA|mRNA]] levels in the brains of [[schizophrenia]] sufferers had been reported in 1998<ref name="szproof1" /> and 2000,<ref name="szproof2" /> and independently confirmed in postmortem studies of the hippocampus,<ref name="szconfirm1" /> [[cerebellum]],<ref name="pmid15560956" /> [[basal ganglia]],<ref name="BDP_basal_ganglia_2007" /> and cerebral cortex.<ref name="szconfirm2" /><ref name="szconfirm3" /> The reduction may reach up to 50% in some brain regions and is coupled with reduced expression of [[GAD-67]] [[enzyme]],<ref name="pmid15560956" /> which catalyses the transition of [[glutamate]] to [[GABA]]. [[Blood test|Blood levels]] of reelin and its [[isoform]]s are also altered in schizophrenia, along with [[mood disorder]]s, according to one study.<ref name="fatemi_blood_reelin" /> 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.<ref name="Knable_2001" />

[[Epigenetics|Epigenetic]] hypermethylation of DNA in schizophrenia patients is proposed as a cause of the reduction,<ref name="hypermeth" /><ref name="dong" /> in agreement with the observations dating from the 1960s that administration of [[methionine]] to schizophrenic patients results in a profound exacerbation of schizophrenia symptoms in sixty to seventy percent of patients.<ref name="methionine1" /><ref name="methionine2" /><ref name="methionine3" /><ref name="methionine4" /> The proposed mechanism is a part of the "epigenetic hypothesis for schizophrenia pathophysiology" formulated by a group of scientists in 2008 (D. Grayson; A. Guidotti; [[Erminio Costa|E. Costa]]).<ref name="Schizophrenia Research Forum: Current Hypotheses" /><ref name="pmid19395859" /> A postmortem study comparing a [[DNA methyltransferase]] ([[DNA methyltransferase#DNMT 1|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.<ref name="epigenetic2007" /> There is evidence that the change is selective, and DNMT1 is overexpressed in reelin-secreting GABAergic neurons but not in their glutamatergic neighbours.<ref name="DNMT_inhibition_GAD67_Reelin_2004" /><ref name="pmid15684088" /> [[Methylation]] inhibitors and [[histone deacetylase]] inhibitors, such as [[valproic acid]], increase reelin mRNA levels,<ref name="valpro" /><ref name="valproicreelin" /><ref name="Mitchell" /> while L-methionine treatment downregulates the phenotypic expression of reelin.<ref name="l-meth" />

One study indicated the upregulation of histone deacetylase HDAC1 in the hippocampi of patients.<ref name="pmid17553960" /> Histone deacetylases suppress gene promoters; hyperacetylation of histones was shown in murine models to demethylate the promoters of both reelin and GAD67.<ref name="Dong_2007" /> DNMT1 inhibitors in animals have been shown to increase the expression of both reelin and GAD67,<ref name="DNMT_inhibition_GAD67_Reelin_2006" /> and both DNMT inhibitors and HDAC inhibitors shown in one study<ref name="pmid19029285" /> to activate both genes with comparable dose- and time-dependence. As one study shows, [[S-adenosyl methionine]] (SAM) concentration in patients' prefrontal cortex is twice as high as in the cortices of non-affected people.<ref name="SAM_and_DNMT1_psychosis_2007" /> SAM, being a methyl group donor necessary for DNMT activity, could further shift epigenetic control of gene expression.{{citation needed|date=January 2016}}

Chromosome region [[7q22]] that harbours the ''RELN'' gene is associated with schizophrenia,<ref name="pmid17684500" /> and the gene itself was associated with the disease in a large study that found the polymorphism [[rs7341475]] to increase the risk of the disease in women, but not in men. The women that have the [[single-nucleotide polymorphism]] (SNP) are about 1.4 times more likely to get ill, according to the study.<ref name="pmid18282107" /> Allelic variations of RELN have also been correlated with working memory, memory and executive functioning in nuclear families where one of the members suffers from schizophrenia.<ref name="pmid17684500" /> The association with working memory was later replicated.<ref name="pmid19922905" /> In one small study, nonsynonymous polymorphism [[Val997Leu]] of the gene was associated with left and right ventricular enlargement in patients.<ref name="pmid19054571" />

One study showed that patients have decreased levels of one of reelin receptors, [[VLDLR]], in the peripheral [[lymphocyte]]s.<ref name="pmid17936586" /> After six months of [[antipsychotic]] therapy the expression went up; according to authors, peripheral VLRLR levels may serve as a reliable peripheral biomarker of schizophrenia.<ref name="pmid17936586" />

Considering the role of reelin in promoting dendritogenesis,<ref name="Niu_2004" /><ref name="pmid18477607" /> suggestions were made that the localized dendritic spine deficit observed in schizophrenia<ref name="pmid18463626" /><ref name="pmid10632234" /> could be in part connected with the downregulation of reelin.<ref name="pmid10725376" /><ref name="pmid11592844" />

Reelin pathway could also be linked to schizophrenia and other psychotic disorders through its interaction with risk genes. One example is the neuronal transcription factor [[NPAS3]], disruption of which is linked to schizophrenia<ref name="Kamnasaran_2003" /> and learning disability. Knockout mice lacking NPAS3 or the similar protein [[NPAS1]] have significantly lower levels of reelin;<ref name="Erbel-Sieler_NPAS3_deficient_mice_2004" /> the precise mechanism behind this is unknown. Another example is the schizophrenia-linked gene [[MTHFR]], with murine knockouts showing decreased levels of reelin in the cerebellum.<ref name="pmid15979267" /> Along the same line, it is worth noting that the gene coding for the subunit [[GRIN2B|NR2B]] that is presumably affected by reelin in the process of NR2B->NR2A developmental change of NMDA receptor composition,<ref name="pmid17881522" /> stands as one of the strongest risk [[Candidate gene|gene candidates]].<ref name="GRIN2B_SZ_GENE_DB" /> Another shared aspect between NR2B and RELN is that they both can be regulated by the [[TBR1]] transcription factor.<ref name="pmid15066269" />

The [[Zygosity|heterozygous]] reeler mouse, which is [[Haploinsufficiency|haploinsufficient]] for the RELN gene, shares several neurochemical and behavioral abnormalities with schizophrenia and bipolar disorder,<ref name="HRM_shared_abnormalities_with_SZ" /> but the exact relevance of these murine behavioral changes to the pathophysiology of schizophrenia remains debatable.<ref name="HRM_not_SZ" />

As previously described, reelin plays a crucial role in modulating early neuroblast migration during brain development. Evidences of altered neural cell positioning in post-mortem schizophrenia patient brains<ref>{{cite journal | vauthors = Akbarian S, Kim JJ, Potkin SG, Hetrick WP, Bunney WE, Jones EG | title = Maldistribution of interstitial neurons in prefrontal white matter of the brains of schizophrenic patients | journal = Archives of General Psychiatry | volume = 53 | issue = 5 | pages = 425–36 | date = May 1996 | pmid = 8624186 | doi=10.1001/archpsyc.1996.01830050061010}}</ref><ref>{{cite journal | vauthors = Joshi D, Fung SJ, Rothwell A, Weickert CS | title = Higher gamma-aminobutyric acid neuron density in the white matter of orbital frontal cortex in schizophrenia | journal = Biological Psychiatry | volume = 72 | issue = 9 | pages = 725–33 | date = November 2012 | pmid = 22841514 | doi = 10.1016/j.biopsych.2012.06.021 | s2cid = 8400626 }}</ref> and changes to [[gene regulatory network]]s that control [[cell migration]]<ref name=":1">{{cite journal|vauthors=Matigian N, Abrahamsen G, Sutharsan R, Cook AL, Vitale AM, Nouwens A, Bellette B, An J, Anderson M, Beckhouse AG, Bennebroek M, Cecil R, Chalk AM, Cochrane J, Fan Y, Féron F, McCurdy R, McGrath JJ, Murrell W, Perry C, Raju J, Ravishankar S, Silburn PA, Sutherland GT, Mahler S, Mellick GD, Wood SA, Sue CM, Wells CA, Mackay-Sim A|date=2010|title=Disease-specific, neurosphere-derived cells as models for brain disorders|journal=Disease Models & Mechanisms|volume=3|issue=11–12|pages=785–98|doi=10.1242/dmm.005447|pmid=20699480|doi-access=free|url=https://eprints.gla.ac.uk/85448/1/85448.pdf}}</ref><ref>{{cite journal | vauthors = Topol A, Zhu S, Hartley BJ, English J, Hauberg ME, Tran N, Rittenhouse CA, Simone A, Ruderfer DM, Johnson J, Readhead B, Hadas Y, Gochman PA, Wang YC, Shah H, Cagney G, Rapoport J, Gage FH, Dudley JT, Sklar P, Mattheisen M, Cotter D, Fang G, Brennand KJ | title = Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells | journal = Cell Reports | volume = 15 | issue = 5 | pages = 1024–1036 | date = May 2016 | pmid = 27117414 | pmc = 4856588 | doi = 10.1016/j.celrep.2016.03.090 }}</ref> suggests a potential link between altered reelin expression in patient brain tissue to disrupted cell migration during brain development. To model the role of reelin in the context of schizophrenia at a cellular level, olfactory neurosphere-derived cells were generated from the [[Nose|nasal]] [[Biopsy|biopsies]] of schizophrenia patients, and compared to cells from healthy controls.<ref name=":1" /> Schizophrenia patient-derived cells have reduced levels of reelin mRNA<ref name=":1" /> and protein<ref name=":2">{{cite journal | vauthors = Tee JY, Sutharsan R, Fan Y, Mackay-Sim A | title = Schizophrenia patient-derived olfactory neurosphere-derived cells do not respond to extracellular reelin | journal = npj Schizophrenia | volume = 2 | pages = 16027 | date = 2016 | pmid = 27602387 | pmc = 4994154 | doi = 10.1038/npjschz.2016.27 }}</ref> when compared to healthy control cells, but expresses the key reelin receptors and DAB1 accessory protein.<ref name=":2" /> When grown ''[[in vitro]]'', schizophrenia patient-derived cells were unable to respond to reelin coated onto [[tissue culture]] surfaces; In contrast, cells derived from healthy controls were able to alter their cell migration when exposed to reelin.<ref name=":2" /> This work went on to show that the lack of cell migration response in patient-derived cells were caused by the cell's inability to produce enough [[focal adhesion]]s of the appropriate size when in contact with extracellular reelin.<ref name=":2" /> More research into schizophrenia cell-based models are needed to look at the function of reelin, or lack of, in the pathophysiology of schizophrenia.

=== Bipolar disorder ===
Decrease in RELN expression with concurrent upregulation of [[DNMT1]] is typical of [[bipolar disorder]] with psychosis, but is not characteristic of patients with major depression without psychosis, which could speak of specific association of the change with psychoses.<ref name="szproof2" /> One study suggests that unlike in schizophrenia, such changes are found only in the cortex and do not affect the deeper structures in psychotic bipolar patients, as their basal ganglia were found to have the normal levels of DNMT1 and subsequently both the reelin and GAD67 levels were within the normal range.<ref name="BDP_basal_ganglia_2007" />

In a genetic study conducted in 2009, preliminary evidence requiring further [[DNA replication]] suggested that variation of the RELN [[gene]] (SNP [[rs362719]]) may be associated with susceptibility to [[bipolar disorder]] in women.<ref name="BipWoman09" />

===Autism===
{{main|Heritability of autism}}

[[Autism spectrum|Autism]] is a [[neurodevelopmental disorder]] that is generally believed to be caused by mutations in several locations, likely triggered by environmental factors. The role of reelin in autism is not decided yet.<ref>{{cite journal | vauthors = Lammert DB, Howell BW | title = RELN Mutations in Autism Spectrum Disorder | journal = Frontiers in Cellular Neuroscience | volume = 10 | issue = 84 | pages = 84 | date = 31 March 2016 | pmid = 27064498 | pmc = 4814460 | doi = 10.3389/fncel.2016.00084 | doi-access = free }}</ref>

Reelin was originally in 2001 implicated in a study finding associations between autism and a [[polymorphism (biology)|polymorphic]] GGC/CGG [[repeated sequence (DNA)|repeat]] preceding the 5' ATG initiator codon of the RELN gene in an Italian population. Longer triplet repeats in the 5' region were associated with an increase in autism susceptibility.<ref name="pmid11317216" /> However, another study of 125 multiple-incidence families and 68 single-incidence families from the subsequent year found no significant difference between the length of the polymorphic repeats in affected and controls. Although, using a family based association test larger ''reelin'' alleles were found to be transmitted more frequently than expected to affected children.<ref name="pmid12399956" /> An additional study examining 158 subjects with German lineage likewise found no evidence of triplet repeat polymorphisms associated with autism.<ref name="pmid14515139" /> And a larger study from 2004 consisting of 395 families found no association between autistic subjects and the CGG triplet repeat as well as the allele size when compared to age of first word.<ref name="pmid15048647" />
In 2010 a large study using data from 4 European cohorts would find some evidence for an association between autism and the [[rs362780]] RELN polymorphism.<ref name="pmid20442744"/>

Studies of [[genetically modified organism|transgenic]] mice have been suggestive of an association, but not definitive.<ref name="pmid17919129" />

===Temporal lobe epilepsy: granule cell dispersion===
Decreased reelin expression in the hippocampal tissue samples from patients with [[temporal lobe epilepsy]] was found to be directly correlated with the extent of [[granule cell]] dispersion (GCD), a major feature of the disease that is noted in 45%–73% of patients.<ref name="TLE1" /><ref name="TLE2" /> The dispersion, according to a small study, is associated with the RELN promoter hypermethylation.<ref name="pmid19287316" /> 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.<ref name="Gonq_2007" /> Moreover, in a [[kainate]]-induced mouse epilepsy model, exogenous reelin had prevented GCD, according to one study.<ref name="pmid19185570" />

===Alzheimer's disease===
The Reelin receptors [[ApoER2]] and [[VLDLR]] belong to the [[LDL]] receptor gene family.<ref name="pmid11252768" /> All members of this family are receptors for [[Apolipoprotein E]] (ApoE). Therefore, they are often synonymously referred to as 'ApoE receptors'. ApoE occurs in 3 common isoforms (E2, E3, E4) in the human population. [[ApoE4]] is the primary genetic risk factor for late-onset [[Alzheimer's disease]]. This strong genetic association has led to the proposal that ApoE receptors play a central role in the pathogenesis of Alzheimer's disease.<ref name="pmid11252768" /><ref name="pmid17053810" /> 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.<ref name="alz" /> This finding is in agreement with an earlier study showing the presence of Reelin associated with amyloid plaques in a transgenic AD mouse model.<ref name="alzmouse" /> A large genetic study of 2008 showed that RELN gene variation is associated with an increased risk of Alzheimer's disease in women.<ref name="pmid18599960" /> The number of reelin-producing Cajal-Retzius cells is significantly decreased in the first cortical layer of patients.<ref name="pmid16051543" /><ref name="pmid17453452" /> Reelin has been shown to interact with [[amyloid precursor protein]],<ref name="pmid19515914" /> and, according to one in-vitro study, is able to counteract the Aβ-induced dampening of [[NMDA-receptor]] activity.<ref name="Herz2009relnabeta" /> This is modulated by ApoE isoforms, which selectively alter the recycling of ApoER2 as well as AMPA and NMDA receptors.<ref name="pmid20547867" />

=== Cancer ===
[[DNA methylation]] patterns are often changed in tumours, and the RELN gene could be affected: according to one study, in the [[pancreatic cancer]] the expression is suppressed, along with other reelin pathway components<ref name="Pancreatic_Cancer_2006" /> In the same study, cutting the reelin pathway in cancer cells that still expressed reelin resulted in increased motility and invasiveness. On the contrary, in [[prostate cancer]] the RELN expression is excessive and correlates with [[Gleason score]].<ref name="Prostate_Cancer_2007_1" /> [[Retinoblastoma]] presents another example of RELN overexpression.<ref name="pmid17615543" /> This gene has also been seen recurrently mutated in cases of [[acute lymphoblastic leukaemia]].<ref name="doi.10.1038/nature10725">{{cite journal | vauthors = Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D, Easton J, Chen X, Wang J, Rusch M, Lu C, Chen SC, Wei L, Collins-Underwood JR, Ma J, Roberts KG, Pounds SB, Ulyanov A, Becksfort J, Gupta P, Huether R, Kriwacki RW, Parker M, McGoldrick DJ, Zhao D, Alford D, Espy S, Bobba KC, Song G, Pei D, Cheng C, Roberts S, Barbato MI, Campana D, Coustan-Smith E, Shurtleff SA, Raimondi SC, Kleppe M, Cools J, Shimano KA, Hermiston ML, Doulatov S, Eppert K, Laurenti E, Notta F, Dick JE, Basso G, Hunger SP, Loh ML, Devidas M, Wood B, Winter S, Dunsmore KP, Fulton RS, Fulton LL, Hong X, Harris CC, Dooling DJ, Ochoa K, Johnson KJ, Obenauer JC, Evans WE, Pui CH, Naeve CW, Ley TJ, Mardis ER, Wilson RK, Downing JR, Mullighan CG | title = The genetic basis of early T-cell precursor acute lymphoblastic leukaemia | journal = Nature | volume = 481 | issue = 7380 | pages = 157–63 | date = January 2012 | pmid = 22237106 | pmc = 3267575 | doi = 10.1038/nature10725 | bibcode = 2012Natur.481..157Z }}</ref>

=== Other conditions ===
One [[genome-wide association study]] indicates a possible role for RELN gene variation in [[otosclerosis]], an abnormal growth of bone of the [[middle ear]].<ref name="pmid19230858" /> In a statistical search for the genes that are differentially expressed in the brains of cerebral malaria-resistant versus cerebral malaria-susceptible mice, Delahaye et al. detected a significant upregulation of both RELN and [[DAB1]] and speculated on possible protective effects of such over-expression.<ref name="pmid18062806" /> In 2020, a study reported a novel variant in ''RELN'' gene (S2486G) which was associated with [[ankylosing spondylitis]] in a large family. This suggested a potential insight into the pathophysiological involvement of reelin via inflammation and osteogenesis pathways in ankylosing spondylitis, and it could broaden the horizon toward new therapeutic strategies.<ref>{{cite journal | vauthors = Garshasbi M, Mahmoudi M, Razmara E, Vojdanian M, Aslani S, Farhadi E, Jensen LR, Arzaghi SM, Poursani S, Bitaraf A, Eidi M, Gharehdaghi EE, Kuss AW, Jamshidi A | title = Identification of RELN variant p.(Ser2486Gly) in an Iranian family with ankylosing spondylitis; the first association of RELN and AS | journal = European Journal of Human Genetics | volume = 28 | issue = 6 | pages = 754–762 | date = June 2020 | pmid = 32001840 | pmc = 7253431 | doi = 10.1038/s41431-020-0573-4 }}</ref> A 2020 study from UT Southwestern Medical Center suggests circulating Reelin levels might correlate with MS severity and stages, and that lowering Reelin levels might be a novel way to treat MS.<ref>{{Cite web|url=https://neurosciencenews.com/reelin-multiple-sclerosis-16819/|title = 'Reelin' in a New Treatment for Multiple Sclerosis|date = 12 August 2020}}</ref>

== Factors affecting reelin expression ==
[[File:Differential reelin levels in the cortex of adult high and low LG rats.gif|thumb|330px|Increased cortical reelin expression in the pups of "High LG" (licking and grooming) rats. A figure from Smit-Righter et al., 2009<ref name="pmid19357777" />]]
The expression of reelin is controlled by a number of factors besides the sheer number of Cajal-Retzius cells. For example, [[TBR1]] transcription factor regulates RELN along with other [[T-element]]-containing genes.<ref name="pmid15066269" /> On a higher level, increased maternal care was found to correlate with reelin expression in rat pups; such correlation was reported in hippocampus<ref name="pmid16484373" /> and in the cortex.<ref name="pmid19357777" /> According to one report, prolonged exposure to [[corticosterone]] significantly decreased reelin expression in murine hippocampi, a finding possibly pertinent to the hypothetical role of [[corticosteroids]] in [[Clinical depression|depression]].<ref name="pmid19477232" /> One small postmortem study has found increased methylation of RELN gene in the neocortex of persons past their puberty compared with those that had yet to enter the period of maturation.<ref name="pmid19952965" />

===Psychotropic medication===
As reelin is being implicated in a number of brain disorders and its expression is usually measured posthumously, assessing the possible medication effects is important.<ref>{{cite journal | vauthors = Ishii K, Kubo KI, Nakajima K | title = Reelin and Neuropsychiatric Disorders | journal = Frontiers in Cellular Neuroscience | volume = 10 | pages = 229 | date = 2016-10-18 | pmid = 27803648 | pmc = 5067484 | doi = 10.3389/fncel.2016.00229 | doi-access = free }}</ref>

According to the epigenetic hypothesis, drugs that shift the balance in favour of [[demethylation]] have a potential to alleviate the proposed methylation-caused downregulation of RELN and GAD67. In one study, clozapine and sulpiride but not haloperidol and olanzapine were shown to increase the demethylation of both genes in mice pretreated with l-methionine.<ref name="pmid18757738" /> [[Valproic acid]], a [[histone deacetylase inhibitor]], when taken in combination with antipsychotics, is proposed to have some benefits. But there are studies conflicting the main premise of the epigenetic hypothesis, and a study by Fatemi et al. shows no increase in RELN expression by valproic acid; that indicates the need for further investigation.{{citation needed|date=January 2016}}

Fatemi et al. conducted the study in which RELN mRNA and reelin protein levels were measured in rat prefrontal cortex following a 21-day of [[intraperitoneal injection]]s of the following drugs:<ref name="Reelin_book_2008" />

{| class="wikitable" style="text-align:center"
|-
! style="width:125px;"| Reelin expression
! style="width:85px;"| [[Clozapine]]
! style="width:85px;"| [[Fluoxetine]]
! style="width:85px;"| [[Haloperidol]]
! style="width:85px;"| [[Lithium (medication)|Lithium]]
! style="width:85px;"| [[Olanzapine]]
! style="width:85px;"| [[Valproic Acid]]
|-
| protein || '''↓''' || '''↔''' || '''↓''' || '''↓''' || '''↑''' || '''↔'''
|-
| mRNA || '''↑''' || '''↑''' || '''↓''' || '''↑''' || '''↑''' || '''↓'''
|}
In 2009, Fatemi et al. published the more detailed work on rats using the same medication. Here, cortical expression of several participants ([[VLDLR]], [[DAB1]], [[GSK3B]]) of the signaling chain was measured besides reelin itself, and also the expression of [[GAD65]] and [[GAD67]].<ref name="pmid19359144" />

== References ==
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<ref name="pmid20442744" >{{cite journal | vauthors = Holt R, Barnby G, Maestrini E, Bacchelli E, Brocklebank D, Sousa I, Mulder EJ, Kantojärvi K, Järvelä I, Klauck SM, Poustka F, Bailey AJ, Monaco AP | title = Linkage and candidate gene studies of autism spectrum disorders in European populations | journal = European Journal of Human Genetics | volume = 18 | issue = 9 | pages = 1013–9 | date = September 2010 | pmid = 20442744 | pmc = 2987412 | doi = 10.1038/ejhg.2010.69 }}</ref>

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<ref name="LTP1">{{cite journal | vauthors = Weeber EJ, Beffert U, Jones C, Christian JM, Forster E, Sweatt JD, Herz J | title = Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning | journal = The Journal of Biological Chemistry | volume = 277 | issue = 42 | pages = 39944–52 | date = October 2002 | pmid = 12167620 | doi = 10.1074/jbc.M205147200 | doi-access = free }}</ref>

<ref name="LTP2">{{cite journal | vauthors = D'Arcangelo G | title = Apoer2: a reelin receptor to remember | journal = Neuron | volume = 47 | issue = 4 | pages = 471–3 | date = August 2005 | pmid = 16102527 | doi = 10.1016/j.neuron.2005.08.001 | s2cid = 15091293 | doi-access = free }}</ref>

<ref name="Niu_2004">{{cite journal | vauthors = 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 | date = January 2004 | pmid = 14715136 | doi = 10.1016/S0896-6273(03)00819-5 | s2cid = 10716252 | doi-access = free }}</ref>

<ref name="pmid18842893">{{cite journal | vauthors = Niu S, Yabut O, D'Arcangelo G | title = The Reelin signaling pathway promotes dendritic spine development in hippocampal neurons | journal = The Journal of Neuroscience | volume = 28 | issue = 41 | pages = 10339–48 | date = October 2008 | pmid = 18842893 | pmc = 2572775 | doi = 10.1523/JNEUROSCI.1917-08.2008 }}</ref>

<ref name="Schizophrenia Research Forum: Current Hypotheses">{{cite web | url = http://www.schizophreniaforum.org/for/curr/grayson/default.asp | title = Current Hypotheses | vauthors = Grayson DR, Guidotti A, Costa E | date = 17 January 2008 | work = Schizophrenia Research Forum | publisher = schizophreniaforum.org | access-date = 23 August 2008 | url-status = dead | archive-url = https://web.archive.org/web/20080917064917/http://www.schizophreniaforum.org/for/curr/grayson/default.asp | archive-date = 17 September 2008 | df = dmy-all }}</ref>

<ref name="pmid19395859">{{cite journal | vauthors = Grayson DR, Chen Y, Dong E, Kundakovic M, Guidotti A | title = From trans-methylation to cytosine methylation: evolution of the methylation hypothesis of schizophrenia | journal = Epigenetics | volume = 4 | issue = 3 | pages = 144–9 | date = April 2009 | pmid = 19395859 | doi = 10.4161/epi.4.3.8534 | doi-access = free }}</ref>

<ref name="pmid17870056">{{cite journal | vauthors = Tochigi M, Iwamoto K, Bundo M, Komori A, Sasaki T, Kato N, Kato T | title = Methylation status of the reelin promoter region in the brain of schizophrenic patients | journal = Biological Psychiatry | volume = 63 | issue = 5 | pages = 530–3 | date = March 2008 | pmid = 17870056 | doi = 10.1016/j.biopsych.2007.07.003 | s2cid = 11816759 }}</ref>

<ref name="pmid18319075">{{cite journal | vauthors = Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L, Jia P, Assadzadeh A, Flanagan J, Schumacher A, Wang SC, Petronis A | title = Epigenomic profiling reveals DNA-methylation changes associated with major psychosis | journal = American Journal of Human Genetics | volume = 82 | issue = 3 | pages = 696–711 | date = March 2008 | pmid = 18319075 | pmc = 2427301 | doi = 10.1016/j.ajhg.2008.01.008 }}</ref>

<ref name="falconer">{{Cite journal | vauthors = Falconer DS |date=January 1951 | title = Two new mutants, 'trembler' and 'reeler', with neurological actions in the house mouse (Mus musculus L.) | journal = Journal of Genetics | volume = 50 | issue = 2 | pages = 192–201 | doi = 10.1007/BF02996215 |pmid=24539699 |s2cid=37918631 | url = http://www.ias.ac.in/jarch/jgenet/50/192.pdf }}</ref>

<ref name="pmid16769115">{{cite journal | vauthors = Tueting P, Doueiri MS, Guidotti A, Davis JM, Costa E | title = Reelin down-regulation in mice and psychosis endophenotypes | journal = Neuroscience and Biobehavioral Reviews | volume = 30 | issue = 8 | pages = 1065–77 | year = 2006 | pmid = 16769115 | doi = 10.1016/j.neubiorev.2006.04.001 | s2cid = 21156214 }}</ref>

<ref name="hamburgh">{{cite journal | vauthors = Hamburgh M | journal = Developmental Biology | volume = 8 | issue = 2 | pages = 165–85 | date = October 1963 | pmid = 14069672 | doi = 10.1016/0012-1606(63)90040-X | title = Analysis of the postnatal developmental effects of "reeler," a neurological mutation in mice. A study in developmental genetics }}</ref>

<ref name="caviness">{{cite journal | vauthors = Caviness VS | title = Patterns of cell and fiber distribution in the neocortex of the reeler mutant mouse | journal = The Journal of Comparative Neurology | volume = 170 | issue = 4 | pages = 435–47 | date = December 1976 | pmid = 1002868 | doi = 10.1002/cne.901700404 | s2cid = 34383977 }}</ref>

<ref name="pmid7972007">{{cite journal | vauthors = Miao GG, Smeyne RJ, D'Arcangelo G, Copeland NG, Jenkins NA, Morgan JI, Curran T | title = Isolation of an allele of reeler by insertional mutagenesis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 23 | pages = 11050–4 | date = November 1994 | pmid = 7972007 | pmc = 45164 | doi = 10.1073/pnas.91.23.11050 | bibcode = 1994PNAS...9111050M | doi-access = free }}</ref>

<ref name="Darcan1">{{cite journal | vauthors = 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 | date = April 1995 | pmid = 7715726 | doi = 10.1038/374719a0 | bibcode = 1995Natur.374..719D | s2cid = 4266946 }}</ref>

<ref name="cr50">{{cite journal | vauthors = Ogawa M, Miyata T, Nakajima K, Yagyu K, Seike M, Ikenaka K, Yamamoto H, Mikoshiba K | 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 | date = May 1995 | pmid = 7748558 | doi = 10.1016/0896-6273(95)90329-1 | s2cid = 17993812 | doi-access = free }}</ref>

<ref name="pmid9837937">{{cite journal | vauthors = Trommsdorff M, Borg JP, Margolis B, Herz J | title = Interaction of cytosolic adaptor proteins with neuronal apolipoprotein E receptors and the amyloid precursor protein | journal = The Journal of Biological Chemistry | volume = 273 | issue = 50 | pages = 33556–60 | date = December 1998 | pmid = 9837937 | doi = 10.1074/jbc.273.50.33556 | doi-access = free }}</ref>

<ref name="receptors_discovery">{{cite journal | vauthors = Trommsdorff M, Gotthardt M, Hiesberger T, Shelton J, Stockinger W, Nimpf J, Hammer RE, Richardson JA, Herz J | 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 | date = June 1999 | pmid = 10380922 | doi = 10.1016/S0092-8674(00)80782-5 | s2cid = 13492626 | doi-access = free }}</ref>

<ref name="yotari_and_scrambler">{{cite journal | vauthors = Sheldon M, Rice DS, D'Arcangelo G, Yoneshima H, Nakajima K, Mikoshiba K, Howell BW, Cooper JA, Goldowitz D, Curran T | 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 | date = October 1997 | pmid = 9338784 | doi = 10.1038/39601 | bibcode = 1997Natur.389..730S | s2cid = 4414738 }}</ref>

<ref name="reelin_G_scholar_search_title">[https://scholar.google.com/scholar?as_q=reelin&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=title&as_sauthors=&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en&lr=&safe=off "Reelin" mentioned in the titles of scientific literature] – a search in the [[Google Scholar]]</ref>

<ref name="Reelin_book_2008">{{cite book | editor = Hossein S. Fatemi | title = Reelin Glycoprotein: Structure, Biology and Roles in Health and Disease | publisher = Springer | year = 2008 | page = 444 | isbn = 978-0-387-76760-4 }}</ref>

<ref name="golgi">{{cite journal | vauthors = 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 = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 7 | pages = 3556–61 | date = March 2000 | pmid = 10725375 | pmc = 16278 | doi = 10.1073/pnas.050589597 | bibcode = 2000PNAS...97.3556L | doi-access = free }}</ref>

<ref name="cr_cells">{{cite journal | vauthors = 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 = Cerebral Cortex | volume = 9 | issue = 8 | pages = 765–75 | date = December 1999 | pmid = 10600995 | doi = 10.1093/cercor/9.8.765 | doi-access =  }}</ref>

<ref name="pmid9671277">{{cite journal | vauthors = Meyer G, Goffinet AM | title = Prenatal development of reelin-immunoreactive neurons in the human neocortex | journal = The Journal of Comparative Neurology | volume = 397 | issue = 1 | pages = 29–40 | date = July 1998 | pmid = 9671277 | doi = 10.1002/(SICI)1096-9861(19980720)397:1<29::AID-CNE3>3.3.CO;2-7 }}</ref>

<ref name="Schiffmann">{{cite journal | vauthors = Schiffmann SN, Bernier B, Goffinet AM | title = Reelin mRNA expression during mouse brain development | journal = The European Journal of Neuroscience | volume = 9 | issue = 5 | pages = 1055–71 | date = May 1997 | pmid = 9182958 | doi = 10.1111/j.1460-9568.1997.tb01456.x | s2cid = 22576790 }}</ref>

<ref name="Interneurons">{{cite journal | vauthors = Pesold C, Impagnatiello F, Pisu MG, Uzunov DP, Costa E, Guidotti A, Caruncho HJ | title = Reelin is preferentially expressed in neurons synthesizing gamma-aminobutyric acid in cortex and hippocampus of adult rats | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 6 | pages = 3221–6 | date = March 1998 | pmid = 9501244 | pmc = 19723 | doi = 10.1073/pnas.95.6.3221 | bibcode = 1998PNAS...95.3221P | doi-access = free }}</ref>

<ref name="Regional_patterns_1998">{{cite journal | vauthors = Alcántara S, Ruiz M, D'Arcangelo G, Ezan F, de Lecea L, Curran T, Sotelo C, Soriano E | title = Regional and cellular patterns of reelin mRNA expression in the forebrain of the developing and adult mouse | journal = The Journal of Neuroscience | volume = 18 | issue = 19 | pages = 7779–99 | date = October 1998 | pmid = 9742148 | pmc = 6792998 | doi = 10.1523/JNEUROSCI.18-19-07779.1998 }}</ref>

<ref name="No_parvalbumin_1999">{{cite journal | vauthors = 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 = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 6 | pages = 3217–22 | date = March 1999 | pmid = 10077664 | pmc = 15922 | doi = 10.1073/pnas.96.6.3217 | bibcode = 1999PNAS...96.3217P | doi-access = free }}</ref>

<ref name="pmid19543540">{{cite journal | vauthors = Suárez-Solá ML, González-Delgado FJ, Pueyo-Morlans M, Medina-Bolívar OC, Hernández-Acosta NC, González-Gómez M, Meyer G | title = Neurons in the white matter of the adult human neocortex | journal = Frontiers in Neuroanatomy | volume = 3 | pages = 7 | year = 2009 | pmid = 19543540 | pmc = 2697018 | doi = 10.3389/neuro.05.007.2009 | doi-access = free }}</ref>

<ref name="bodyexpr">{{cite journal | vauthors = Smalheiser NR, Costa E, Guidotti A, Impagnatiello F, Auta J, Lacor P, Kriho V, Pappas GD | title = Expression of reelin in adult mammalian blood, liver, pituitary pars intermedia, and adrenal chromaffin cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 3 | pages = 1281–6 | date = February 2000 | pmid = 10655522 | pmc = 15597 | doi = 10.1073/pnas.97.3.1281 | bibcode = 2000PNAS...97.1281S | doi-access = free }}</ref>

<ref name="liver2">{{cite journal | vauthors = Samama B, Boehm N | title = Reelin immunoreactivity in lymphatics and liver during development and adult life | journal = The Anatomical Record Part A: Discoveries in Molecular, Cellular, and Evolutionary Biology | volume = 285 | issue = 1 | pages = 595–9 | date = July 2005 | pmid = 15912522 | doi = 10.1002/ar.a.20202 | doi-access = free }}</ref>

<ref name="Kobold_2002_liver1">{{cite journal | vauthors = Kobold D, Grundmann A, Piscaglia F, Eisenbach C, Neubauer K, Steffgen J, Ramadori G, Knittel T | 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 = Journal of Hepatology | volume = 36 | issue = 5 | pages = 607–13 | date = May 2002 | pmid = 11983443 | doi = 10.1016/S0168-8278(02)00050-8 }}</ref>

<ref name="pmid17120005">{{cite journal | vauthors = Pulido JS, Sugaya I, Comstock J, Sugaya K | title = Reelin expression is upregulated following ocular tissue injury | journal = Graefe's Archive for Clinical and Experimental Ophthalmology | volume = 245 | issue = 6 | pages = 889–93 | date = June 2007 | pmid = 17120005 | doi = 10.1007/s00417-006-0458-4 | s2cid = 12397364 }}</ref>

<ref name="pmid10980418">{{cite journal | vauthors = Buchaille R, Couble ML, Magloire H, Bleicher F | title = A substractive PCR-based cDNA library from human odontoblast cells: identification of novel genes expressed in tooth forming cells | journal = Matrix Biology | volume = 19 | issue = 5 | pages = 421–30 | date = September 2000 | pmid = 10980418 | doi = 10.1016/S0945-053X(00)00091-3 }}</ref>

<ref name="pmid16831873">{{cite journal | vauthors = Allard B, Magloire H, Couble ML, Maurin JC, Bleicher F | title = Voltage-gated sodium channels confer excitability to human odontoblasts: possible role in tooth pain transmission | journal = The Journal of Biological Chemistry | volume = 281 | issue = 39 | pages = 29002–10 | date = September 2006 | pmid = 16831873 | doi = 10.1074/jbc.M601020200 | doi-access = free }}</ref>

<ref name="pmid15464360">{{cite journal | vauthors = Maurin JC, Couble ML, Didier-Bazes M, Brisson C, Magloire H, Bleicher F | title = Expression and localization of reelin in human odontoblasts | journal = Matrix Biology | volume = 23 | issue = 5 | pages = 277–85 | date = August 2004 | pmid = 15464360 | doi = 10.1016/j.matbio.2004.06.005 }}</ref>

<ref name="pmid17548821">{{PDB|2E26}}; {{cite journal | vauthors = Yasui N, Nogi T, Kitao T, Nakano Y, Hattori M, Takagi J | title = Structure of a receptor-binding fragment of reelin and mutational analysis reveal a recognition mechanism similar to endocytic receptors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 24 | pages = 9988–93 | date = June 2007 | pmid = 17548821 | pmc = 1891246 | doi = 10.1073/pnas.0700438104 | bibcode = 2007PNAS..104.9988Y | doi-access = free }}</ref>

<ref name="pmid9417911">{{cite journal | vauthors = Royaux I, Lambert de Rouvroit C, D'Arcangelo G, Demirov D, Goffinet AM | title = Genomic organization of the mouse reelin gene | journal = Genomics | volume = 46 | issue = 2 | pages = 240–50 | date = December 1997 | pmid = 9417911 | doi = 10.1006/geno.1997.4983 }}</ref>

<ref name="reelinstructure2006japan">{{PDB|2ddu}}; {{cite journal | vauthors = Nogi T, Yasui N, Hattori M, Iwasaki K, Takagi J | title = Structure of a signaling-competent reelin fragment revealed by X-ray crystallography and electron tomography | journal = The EMBO Journal | volume = 25 | issue = 15 | pages = 3675–83 | date = August 2006 | pmid = 16858396 | pmc = 1538547 | doi = 10.1038/sj.emboj.7601240 }}</ref>

<ref name="Nakano_2007_CTR_1">{{cite journal | vauthors = Nakano Y, Kohno T, Hibi T, Kohno S, Baba A, Mikoshiba K, Nakajima K, Hattori M | title = The extremely conserved C-terminal region of Reelin is not necessary for secretion but is required for efficient activation of downstream signaling | journal = The Journal of Biological Chemistry | volume = 282 | issue = 28 | pages = 20544–52 | date = July 2007 | pmid = 17504759 | doi = 10.1074/jbc.M702300200 | doi-access = free }}</ref>

<ref name="cleave">{{cite journal | vauthors = Lambert de Rouvroit C, de Bergeyck V, Cortvrindt C, Bar I, Eeckhout Y, Goffinet AM | title = Reelin, the extracellular matrix protein deficient in reeler mutant mice, is processed by a metalloproteinase | journal = Experimental Neurology | volume = 156 | issue = 1 | pages = 214–7 | date = March 1999 | pmid = 10192793 | doi = 10.1006/exnr.1998.7007 | s2cid = 35222830 }}</ref>

<ref name="centralfragment">{{cite journal | vauthors = Jossin Y, Ignatova N, Hiesberger T, Herz J, Lambert de Rouvroit C, Goffinet AM | title = The central fragment of Reelin, generated by proteolytic processing in vivo, is critical to its function during cortical plate development | journal = The Journal of Neuroscience | volume = 24 | issue = 2 | pages = 514–21 | date = January 2004 | pmid = 14724251 | pmc = 6730001 | doi = 10.1523/JNEUROSCI.3408-03.2004 }}</ref>

<ref name="pmid17442808">{{cite journal | vauthors = Jossin Y, Gui L, Goffinet AM | title = Processing of Reelin by embryonic neurons is important for function in tissue but not in dissociated cultured neurons | journal = The Journal of Neuroscience | volume = 27 | issue = 16 | pages = 4243–52 | date = April 2007 | pmid = 17442808 | pmc = 6672330 | doi = 10.1523/JNEUROSCI.0023-07.2007 }}</ref>

<ref name="pmid14614786">{{cite journal | vauthors = Lennington JB, Yang Z, Conover JC | title = Neural stem cells and the regulation of adult neurogenesis | journal = Reproductive Biology and Endocrinology | volume = 1 | pages = 99 | date = November 2003 | pmid = 14614786 | pmc = 293430 | doi = 10.1186/1477-7827-1-99 | doi-access = free }}</ref>

<ref name="pmid12925587">{{cite journal | vauthors = Hartfuss E, Förster E, Bock HH, Hack MA, Leprince P, Luque JM, Herz J, Frotscher M, Götz M | title = Reelin signaling directly affects radial glia morphology and biochemical maturation | journal = Development | volume = 130 | issue = 19 | pages = 4597–609 | date = October 2003 | pmid = 12925587 | doi = 10.1242/dev.00654 | doi-access = free | hdl = 10261/333510 | hdl-access = free }}</ref>

<ref name="pmid18197264">{{cite journal | vauthors = Nomura T, Takahashi M, Hara Y, Osumi N | title = Patterns of neurogenesis and amplitude of Reelin expression are essential for making a mammalian-type cortex | journal = PLOS ONE | volume = 3 | issue = 1 | pages = e1454 | date = January 2008 | pmid = 18197264 | pmc = 2175532 | doi = 10.1371/journal.pone.0001454 | bibcode = 2008PLoSO...3.1454N | veditors = Reh T | doi-access = free }}</ref>

<ref name="DerRio1997">{{cite journal | vauthors = Del Río JA, Heimrich B, Borrell V, Förster E, Drakew A, Alcántara S, Nakajima K, Miyata T, Ogawa M, Mikoshiba K, Derer P, Frotscher M, Soriano E | title = A role for Cajal-Retzius cells and reelin in the development of hippocampal connections | journal = Nature | volume = 385 | issue = 6611 | pages = 70–4 | date = January 1997 | pmid = 8985248 | doi = 10.1038/385070a0 | bibcode = 1997Natur.385...70D | s2cid = 4352996 }}</ref>

<ref name="Borrell1999">{{cite journal | vauthors = Borrell V, Del Río JA, Alcántara S, Derer M, Martínez A, D'Arcangelo G, Nakajima K, Mikoshiba K, Derer P, Curran T, Soriano E | title = Reelin regulates the development and synaptogenesis of the layer-specific entorhino-hippocampal connections | journal = The Journal of Neuroscience | volume = 19 | issue = 4 | pages = 1345–58 | date = February 1999 | pmid = 9952412 | pmc = 6786030 | doi =  10.1523/JNEUROSCI.19-04-01345.1999}}</ref>

<ref name="pmid16410414">{{cite journal | vauthors = Yoshida M, Assimacopoulos S, Jones KR, Grove EA | title = Massive loss of Cajal-Retzius cells does not disrupt neocortical layer order | journal = Development | volume = 133 | issue = 3 | pages = 537–45 | date = February 2006 | pmid = 16410414 | doi = 10.1242/dev.02209 | s2cid = 1702450 | doi-access =  }}</ref>

<ref name="pmid19412957">{{cite journal | vauthors = Yip YP, Mehta N, Magdaleno S, Curran T, Yip JW | title = Ectopic expression of reelin alters migration of sympathetic preganglionic neurons in the spinal cord | journal = The Journal of Comparative Neurology | volume = 515 | issue = 2 | pages = 260–8 | date = July 2009 | pmid = 19412957 | doi = 10.1002/cne.22044 | s2cid = 21832778 }}</ref>

<ref name="roleofreelin1">{{cite journal | vauthors = Hack I, Bancila M, Loulier K, Carroll P, Cremer H | title = Reelin is a detachment signal in tangential chain-migration during postnatal neurogenesis | journal = Nature Neuroscience | volume = 5 | issue = 10 | pages = 939–45 | date = October 2002 | pmid = 12244323 | doi = 10.1038/nn923 | s2cid = 7096018 }}</ref>

<ref name="pmid17494763">{{cite journal | vauthors = Andrade N, Komnenovic V, Blake SM, Jossin Y, Howell B, Goffinet A, Schneider WJ, Nimpf J | title = ApoER2/VLDL receptor and Dab1 in the rostral migratory stream function in postnatal neuronal migration independently of Reelin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 20 | pages = 8508–13 | date = May 2007 | pmid = 17494763 | pmc = 1895980 | doi = 10.1073/pnas.0611391104 | bibcode = 2007PNAS..104.8508A | doi-access = free }}</ref>

<ref name="pmid18946489">{{cite journal | vauthors = Blake SM, Strasser V, Andrade N, Duit S, Hofbauer R, Schneider WJ, Nimpf J | title = Thrombospondin-1 binds to ApoER2 and VLDL receptor and functions in postnatal neuronal migration | journal = The EMBO Journal | volume = 27 | issue = 22 | pages = 3069–80 | date = November 2008 | pmid = 18946489 | pmc = 2585172 | doi = 10.1038/emboj.2008.223 }}</ref>

<ref name="dentate_gyrus">{{cite journal | vauthors = Frotscher M, Haas CA, Förster E | title = Reelin controls granule cell migration in the dentate gyrus by acting on the radial glial scaffold | journal = Cerebral Cortex | volume = 13 | issue = 6 | pages = 634–40 | date = June 2003 | pmid = 12764039 | doi = 10.1093/cercor/13.6.634 | doi-access = free }}</ref>

<ref name="OlivierManzoni">[http://www.inb.u-bordeaux2.fr/siteneuro2/pages/UniteINB/Manzoni/Manzoniavenir.htm INSERM – Olivier Manzoni – Physiopathology of Synaptic Transmission and Plasticity] {{webarchive|url=https://web.archive.org/web/20061125230210/http://www.inb.u-bordeaux2.fr/siteneuro2/pages/UniteINB/Manzoni/Manzoniavenir.htm |date=25 November 2006 }} – Bordo neuroscience institute.</ref>

<ref name="pmid15987942">{{cite journal | vauthors = Sinagra M, Verrier D, Frankova D, Korwek KM, Blahos J, Weeber EJ, Manzoni OJ, Chavis P | title = Reelin, very-low-density lipoprotein receptor, and apolipoprotein E receptor 2 control somatic NMDA receptor composition during hippocampal maturation in vitro | journal = The Journal of Neuroscience | volume = 25 | issue = 26 | pages = 6127–36 | date = June 2005 | pmid = 15987942 | pmc = 6725049 | doi = 10.1523/JNEUROSCI.1757-05.2005 }}</ref>

<ref name="pmid17881522">{{cite journal | vauthors = Groc L, Choquet D, Stephenson FA, Verrier D, Manzoni OJ, Chavis P | title = NMDA receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein Reelin | journal = The Journal of Neuroscience | volume = 27 | issue = 38 | pages = 10165–75 | date = September 2007 | pmid = 17881522 | doi = 10.1523/JNEUROSCI.1772-07.2007 | pmc = 6672660 }}</ref>

<ref name="pmid15470155">{{cite journal | vauthors = Liu XB, Murray KD, Jones EG | title = Switching of NMDA receptor 2A and 2B subunits at thalamic and cortical synapses during early postnatal development | journal = The Journal of Neuroscience | volume = 24 | issue = 40 | pages = 8885–95 | date = October 2004 | pmid = 15470155 | pmc = 6729956 | doi = 10.1523/JNEUROSCI.2476-04.2004 }}</ref>

<ref name="pmid19430527">{{cite journal | vauthors = Campo CG, Sinagra M, Verrier D, Manzoni OJ, Chavis P | title = Reelin secreted by GABAergic neurons regulates glutamate receptor homeostasis | journal = PLOS ONE | volume = 4 | issue = 5 | pages = e5505 | year = 2009 | pmid = 19430527 | pmc = 2675077 | doi = 10.1371/journal.pone.0005505 | bibcode = 2009PLoSO...4.5505C | veditors = Okazawa H | doi-access = free }}</ref>

<ref name="pmid11137154">{{cite journal | vauthors = Bar I, Lambert de Rouvroit C, Goffinet AM | title = The evolution of cortical development. An hypothesis based on the role of the Reelin signaling pathway | journal = Trends in Neurosciences | volume = 23 | issue = 12 | pages = 633–8 | date = December 2000 | pmid = 11137154 | doi = 10.1016/S0166-2236(00)01675-1 | s2cid = 13568642 }}</ref>

<ref name="pmid16519657">{{cite journal | vauthors = Molnár Z, Métin C, Stoykova A, Tarabykin V, Price DJ, Francis F, Meyer G, Dehay C, Kennedy H | title = Comparative aspects of cerebral cortical development | journal = The European Journal of Neuroscience | volume = 23 | issue = 4 | pages = 921–34 | date = February 2006 | pmid = 16519657 | pmc = 1931431 | doi = 10.1111/j.1460-9568.2006.04611.x }}</ref>

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<ref name="pmid12899622">{{cite journal | vauthors = Andersen OM, Benhayon D, Curran T, Willnow TE | title = Differential binding of ligands to the apolipoprotein E receptor 2 | journal = Biochemistry | volume = 42 | issue = 31 | pages = 9355–64 | date = August 2003 | pmid = 12899622 | doi = 10.1021/bi034475p }}</ref>

<ref name="pmid12670700">{{cite journal | vauthors = Benhayon D, Magdaleno S, Curran T | title = Binding of purified Reelin to ApoER2 and VLDLR mediates tyrosine phosphorylation of Disabled-1 | journal = Brain Research. Molecular Brain Research | volume = 112 | issue = 1–2 | pages = 33–45 | date = April 2003 | pmid = 12670700 | doi = 10.1016/S0169-328X(03)00032-9 }}</ref>

<ref name="pmid19922905">{{cite journal | vauthors = Wedenoja J, Tuulio-Henriksson A, Suvisaari J, Loukola A, Paunio T, Partonen T, Varilo T, Lönnqvist J, Peltonen L | title = Replication of association between working memory and Reelin, a potential modifier gene in schizophrenia | journal = Biological Psychiatry | volume = 67 | issue = 10 | pages = 983–91 | date = May 2010 | pmid = 19922905 | pmc = 3083525 | doi = 10.1016/j.biopsych.2009.09.026 }}</ref><ref name="pmid11252768">{{cite journal | vauthors = Herz J, Beffert U | title = Apolipoprotein E receptors: linking brain development and Alzheimer's disease | journal = Nature Reviews. Neuroscience | volume = 1 | issue = 1 | pages = 51–8 | date = October 2000 | pmid = 11252768 | doi = 10.1038/35036221 | s2cid = 27105032 }}</ref>

<ref name="pmid17053810">{{cite journal | vauthors = Herz J, Chen Y | title = Reelin, lipoprotein receptors and synaptic plasticity | journal = Nature Reviews. Neuroscience | volume = 7 | issue = 11 | pages = 850–9 | date = November 2006 | pmid = 17053810 | doi = 10.1038/nrn2009 | s2cid = 44317115 }}</ref>

<ref name="pmid20547867">{{cite journal | vauthors = Chen Y, Durakoglugil MS, Xian X, Herz J | title = ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 26 | pages = 12011–6 | date = June 2010 | pmid = 20547867 | pmc = 2900641 | doi = 10.1073/pnas.0914984107 | bibcode = 2010PNAS..10712011C | doi-access = free }}</ref>

<ref name="pmid10571241">{{cite journal | vauthors = Hiesberger T, Trommsdorff M, Howell BW, Goffinet A, Mumby MC, Cooper JA, Herz J | title = Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation | journal = Neuron | volume = 24 | issue = 2 | pages = 481–9 | date = October 1999 | pmid = 10571241 | doi = 10.1016/S0896-6273(00)80861-2 | s2cid = 243043 | doi-access = free }}</ref>

<ref name="pmid10571240">{{cite journal | vauthors = D'Arcangelo G, Homayouni R, Keshvara L, Rice DS, Sheldon M, Curran T | title = Reelin is a ligand for lipoprotein receptors | journal = Neuron | volume = 24 | issue = 2 | pages = 471–9 | date = October 1999 | pmid = 10571240 | doi = 10.1016/S0896-6273(00)80860-0 | s2cid = 14631418 | doi-access = free }}</ref>

}}

== Further reading ==
{{Commons category}}
{{refbegin}}
* {{cite journal | vauthors = Fatemi SH | title = Reelin glycoprotein: structure, biology and roles in health and disease | journal = Molecular Psychiatry | volume = 10 | issue = 3 | pages = 251–257 | date = March 2005 | pmid = 15583703 | doi = 10.1038/sj.mp.4001613 | publisher = Springer | isbn = 978-0-387-76760-4 | s2cid = 21206951 }}
* {{cite journal | vauthors = Förster E, Jossin Y, Zhao S, Chai X, Frotscher M, Goffinet AM | title = Recent progress in understanding the role of Reelin in radial neuronal migration, with specific emphasis on the dentate gyrus | journal = The European Journal of Neuroscience | volume = 23 | issue = 4 | pages = 901–9 | date = February 2006 | pmid = 16519655 | doi = 10.1111/j.1460-9568.2006.04612.x | s2cid = 25269492 }}
* {{cite journal | vauthors = Beffert U, Stolt PC, Herz J | title = Functions of lipoprotein receptors in neurons | journal = Journal of Lipid Research | volume = 45 | issue = 3 | pages = 403–9 | date = March 2004 | pmid = 14657206 | doi = 10.1194/jlr.R300017-JLR200 | doi-access = free }}
* {{cite journal | vauthors = Dong E, Agis-Balboa RC, Simonini MV, Grayson DR, Costa E, Guidotti A | title = Reelin and glutamic acid decarboxylase67 promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 35 | pages = 12578–83 | date = August 2005 | pmid = 16113080 | pmc = 1194936 | doi = 10.1073/pnas.0505394102 | bibcode = 2005PNAS..10212578D | doi-access = free }}
* {{cite journal | vauthors = Magdaleno SM, Curran T | title = Brain development: integrins and the Reelin pathway | journal = Current Biology | volume = 11 | issue = 24 | pages = R1032-5 | date = December 2001 | pmid = 11747842 | doi = 10.1016/S0960-9822(01)00618-2 | s2cid = 8790079 | doi-access = free | bibcode = 2001CBio...11R1032M }}
* {{cite journal | vauthors = Hong SE, Shugart YY, Huang DT, Shahwan SA, Grant PE, Hourihane JO, Martin ND, Walsh CA | title = Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations | journal = Nature Genetics | volume = 26 | issue = 1 | pages = 93–6 | date = September 2000 | pmid = 10973257 | doi = 10.1038/79246 | s2cid = 67748801 }}
{{refend}}

== External links ==
{{wiktionary}}
* {{PDBe-KB2|Q60841|Mouse Reelin}}
* {{cite web | url = http://lifesci.rutgers.edu/~molbiosci/faculty/darcangelo.html | title = Gabriella D'Arcangelo | publisher = Rutgers University | quote = the scientist who discovered the reelin gene and protein | access-date = 23 August 2008 | archive-url = https://web.archive.org/web/20080725055259/http://www.lifesci.rutgers.edu/%7Emolbiosci/faculty/darcangelo.html | archive-date = 25 July 2008 | url-status = dead | df = dmy-all }}
* [https://web.archive.org/web/20170919165819/https://www.wikigenes.org/e/gene/e/5649.html Human RELN at WikiGenes]
* {{cite web | url = http://www.stjudebgem.org/web/view/probe/viewProbeDetails.php?id=404 | archive-url = https://archive.today/20050123114225/http://www.stjudebgem.org/web/view/probe/viewProbeDetails.php?id=404 | url-status = usurped | archive-date = 23 January 2005 | title = Reelin gene expression in mice | work = Brain Gene Expression Map | publisher = St. Jude Children's Research Hospital | access-date = 23 August 2008 }}

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