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Reelin

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RELN
Available structures
PDBOrtholog search:PDBeRCSB
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
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Reelin,encoded by theRELNgene,[5]is a large secretedextracellular matrixglycoproteinthat helps regulate processes ofneuronal migrationand positioning in the developing brain by controllingcell–cell interactions.Besides this important role in earlydevelopment,reelin continues to work in the adult brain.[6]It modulatessynaptic plasticityby enhancing the induction and maintenance oflong-term potentiation.[7][8]It also stimulates dendrite[9]anddendritic spine[10]development and regulates the continuing migration ofneuroblastsgenerated inadult neurogenesissites like thesubventricularandsubgranular zones.It is found not only in thebrainbut also in theliver,thyroid gland,adrenal gland,fallopian tube,breastand in comparatively lower levels across a range of anatomical regions.[11]

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 inschizophreniaand psychoticbipolar disorder,[12]but the cause of this observation remains uncertain, as studies show thatpsychotropic medication itself affects reelin expression.Moreover,epigenetichypotheses aimed at explaining the changed levels of reelin expression[13]are controversial.[14][15]Total lack of reelin causes a form oflissencephaly.Reelin may also play a role inAlzheimer's disease,[16]temporal lobe epilepsyandautism.

Reelin's name comes from the abnormal reelinggaitofreelermice,[17]which were later found to have a deficiency of this brainproteinand werehomozygousfor mutation of the RELN gene. The primary phenotype associated with loss of reelin function is a failure of neuronal positioning throughout the developingcentral nervous system(CNS). The miceheterozygousfor the reelin gene, while having little neuroanatomical defects, display theendophenotypictraits linked to psychotic disorders.[18]

Discovery

[edit]
Video: the reeler mice mutants, first described in 1951 byD.S.Falconer,were later found to lack reelin protein.
Normal andreelermice brain slices.

Mutant mice have provided insight into the underlying molecular mechanisms of the development of thecentral nervous system.Useful spontaneous mutations were first identified by scientists who were interested inmotor behavior,and it proved relatively easy to screenlittermatesfor 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]

The "reeler"mouse was described for the first time in 1951 byD.S.FalconerinEdinburgh Universityas a spontaneous variant arising in a colony of at least mildly inbred snowy-white bellied mice stock in 1948.[17]Histopathologicalstudies in the 1960s revealed that thecerebellumof reeler mice is dramatically decreased in size while the normal laminar organization found in several brain regions is disrupted.[19]The 1970s brought about the discovery of cellular layer inversion in the mouse neocortex,[20]which attracted more attention to the reeler mutation.

In 1994, a newalleleof reeler was obtained by means of insertionalmutagenesis.[21]This provided the firstmolecular markerof thelocus,permitting the RELN gene to be mapped to chromosome 7q22 and subsequently cloned and identified.[22]Japanese scientists atKochi Medical Schoolsuccessfully raised antibodies against normal brain extracts in reeler mice, later these antibodies were found to be specificmonoclonal antibodiesfor reelin, and were termed CR-50 (Cajal-Retzius marker 50).[23]They noted that CR-50 reacted specifically withCajal-Retzius neurons,whose functional role was unknown until then.[citation needed]

The Reelin receptors,apolipoprotein E receptor 2(ApoER2) andvery-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.[24]They then went on to show that the doubleknockoutmice for ApoER2 and VLDLR, which both interact with Dab1, had cortical layering defects similar to those in reeler.[25]

Thedownstreampathwayof reelin was further clarified with the help of other mutant mice, includingyotariandscrambler.These mutants have phenotypes similar to that of reeler mice, but without mutation in reelin. It was then demonstrated that the mousedisabled homologue 1(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.[26]Targeted disruption of Dab1 also caused a phenotype similar to that of reeler. Pinpointing theDAB1as a pivotal regulator of the reelin signaling cascade started the tedious process of deciphering its complex interactions.[citation needed]

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.[27][28]

Tissue distribution and secretion

[edit]

Studies show that reelin is absent fromsynaptic vesiclesand is secreted viaconstitutive secretory pathway,being stored inGolgisecretory vesicles.[29]Reelin's release rate is not regulated bydepolarization,but strictly depends on its synthesis rate. This relationship is similar to that reported for the secretion of otherextracellular matrixproteins.[citation needed]

During the brain development, reelin is secreted in the cortex and hippocampus by the so-calledCajal-Retzius cells,Cajal cells, and Retzius cells.[30]Reelin-expressing cells in the prenatal and early postnatal brain are predominantly found in the marginal zone (MZ) of the cortex and in the temporarysubpial granular layer(SGL), which is manifested to the highest extent in human,[31]and in the hippocampalstratum lacunosum-moleculareand the upper marginal layer of thedentate gyrus.

In the developingcerebellum,reelin is expressed first in the externalgranule celllayer (EGL), before the granule cell migration to the internal granule cell layer (IGL) takes place.[32]

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 byGABA-ergicinterneuronsof the cortex and glutamatergic cerebellar neurons,[33]the glutamatergic stellate cells and fan cells in the superficialentorhinal cortexthat are supposed to carry a role in encoding newepisodic memories,[34]and by the few extant Cajal-Retzius cells. Among GABAergic interneurons, reelin seems to be detected predominantly in those expressingcalretininandcalbindin,likebitufted,horizontal,andMartinotti cells,but notparvalbumin-expressing cells, likechandelierorbasket neurons.[35][36]In the white matter, a minute proportion ofinterstitial neuronshas also been found to stain positive for reelin expression.[37]

Schema of the reelin protein

Outside the brain, reelin is found in adult mammalian blood,liver,pituitarypars intermedia,and adrenalchromaffin cells.[38]In the liver, reelin is localized inhepatic stellate cells.[39]The expression of reelin increases when the liver is damaged, and returns to normal following its repair.[40] In the eyes, reelin is secreted byretinal ganglion cellsand is also found in theendothelial layer of the cornea.[41]Just as in the liver, its expression increases after an injury has taken place.[citation needed]

The protein is also produced by theodontoblasts,which are cells at the margins of the dental pulp. Reelin is found here both during odontogenesis and in the mature tooth.[42]Some authors suggest that odontoblasts play an additional role as sensory cells able totransducepain signals to the nerve endings.[43]According to the hypothesis, reelin participates in the process[28]by enhancing the contact between odontoblasts and the nerve terminals.[44]

Structure

[edit]
The structure of twomurinereelin repeatsas revealed byX-ray crystallography.[45]

Reelin is composed of 3461 amino acids with a relative molecular mass of 388kDa.It also hasserine proteaseactivity.[46]Murine RELN gene consists of 65exonsspanning approximately 450kb.[47]One exon, coding for only two amino acids near the protein'sC-terminus,undergoesalternative splicing,but the exact functional impact of this is unknown.[28]Two transcription initiation sites and two polyadenylation sites are identified in the gene structure.[47]

The reelin protein starts with a signaling peptide 27 amino acids in length, followed by a region bearing similarity toF-spondin(thereeler 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 calledreelin repeatsand have anepidermal growth factormotif at their center, dividing each repeat into two subrepeats,A(theBNR/Asp-box repeat) andB(theEGF-like domain). Despite this interruption, the two subdomains make direct contact, resulting in a compact overall structure.[48]

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 Orleansreelermutation, 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.[49]

Reelin is cleavedin vivoat 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.[50]This splitting does not decrease the protein's activity, as constructs made of the predicted central fragments (repeats 3–6) bind to lipoprotein receptors, triggerDab1phosphorylationand mimic functions of reelin duringcortical platedevelopment.[51]Moreover, the processing of reelin by embryonic neurons may be necessary for proper corticogenesis.[52]

Function

[edit]
As they travel through therostral migratory stream,neuroblasts are held together, probably in part bythrombospondin-1's binding to the reelin receptorsApoER2andVLDLR.[53]As they arrive to the destination, the groups are dispersed by reelin and cells strike out on their individual paths. A fragment of anillustrationfrom Lennington et al., 2003.[54]

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.[11]

During development

[edit]

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 intoradial gliaand affects the orientation of its fibers, which serve as the guides for the migrating neuroblasts.[55]The position of reelin-secreting cell layer is important, because the fibers orient themselves in the direction of its higher concentration.[56]For example, reelin regulates the development of layer-specific connections in hippocampus and entorhinal cortex.[57][58]

Reelin controls the direction of radial glia growth. A fragment of anillustrationfrom Nomura T. et al., 2008.[56]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.

Mammaliancorticogenesisis 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 mutantreelermouse, 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 withCajal-Retzius cellsand some cells normally destined for the second layer.[citation needed]

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 theradial gliafibers that are extending in the direction of reelin-expressing cells. Nomura T. et al., 2008.[56]

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,[59]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,[60]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]

Reelin may also ensure correct neuronal positioning in thespinal cord:according to one study, location and level of its expression affects the movement of sympathetic preganglionic neurons.[61]

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.[59]Dissociation detaches migrating neurons from theglial cellsthat are acting as their guides, converting them into individual cells that can strike out alone to find their final position.[citation needed]

Top: Representative image of somatic reelin immunoreactivities found in 12-day-in-vitro hippocampal neurons. Bottom: reelin immunofluorescence (red) overlaid withMAP2counterstain(green). A fragment of anillustrationfrom Campo et al., 2009.[62]

Reelin takes part in the developmental change ofNMDA receptorconfiguration, increasing mobility ofNR2B-containing receptors and thus decreasing the time they spend at thesynapse.[63][dead link][64][65]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.[66]Ongoing reelin secretion by GABAergic hippocampal neurons is necessary to keep NR2B-containing NMDA receptors at a low level.[62]

In adults

[edit]

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 therostral 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,ApoER2andVLDLR,and their intracellular adapterDAB1function independently of Reelin,[67]most likely by the influence of a newly proposed ligand,thrombospondin-1.[53]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.[68]

Reelin also plays an important role in the adult brain by modulating cortical pyramidal neurondendritic spineexpression density, the branching ofdendrites,and the expression oflong-term potentiation[8]as its secretion is continued diffusely by the GABAergic cortical interneurons those origin is traced to the medialganglionic eminence.

In the adult organism the non-neural expression is much less widespread, but goes up sharply when some organs are injured.[40][41]The exact function of reelin upregulation following an injury is still being researched.[citation needed]

Evolutionary significance

[edit]
Cajal-Retzius cells,as drawn by Cajal in 1891. The development of a distinct layer of these reelin-secreting cells played a major role in brain evolution.
Neuronal development: mammals (left) and avians (right) have different patterns of reelin expression (pink). Nomura T. et al., 2008.[56]

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 theamniotesinto multiple-layered cortex of contemporary mammals.[69]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.[70]Reelin is present in the telencephalon of all the vertebrates studied so far, but the pattern of expression differs widely. For example,zebrafishhave no Cajal-Retzius cells at all; instead, the protein is being secreted by other neurons.[71][72]These cells do not form a dedicated layer in amphibians, and radial migration in their brains is very weak.[71]

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.[56]There are conflicting data concerning the importance of this layer,[60]and these are explained in the literature either by the existence of an additional signaling positional mechanism that interacts with the reelin cascade,[60]or by the assumption that mice that are used in such experiments have redundant secretion of reelin[73]compared with more localized synthesis in the human brain.[31]

Cajal-Retzius cells, most of which disappear around the time of birth, coexpress reelin with theHAR1gene 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 thehuman accelerated regions.[74]There is also evidence of that variants in the DAB1 gene have been included in a recent selective sweep in Chinese populations.[75][76]

Mechanism of action

[edit]
The main reelin signaling cascade (ApoER2 and VLDLR) and its interaction withLIS1.Zhang et al., 2008[77]
SFK:Src family kinases.
JIP:JNK-interacting protein 1

Receptors

[edit]

Reelin's control of cell-cell interactions is thought to be mediated by binding of reelin to the two members oflow density lipoprotein receptor gene family:VLDLRand theApoER2.[78][79][80][81]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.[82]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-1integrinreceptor.[83]The proposal that the protocadherinCNR1 behaves as a Reelin receptor[84]has been disproven.[51]

As members of lipoprotein receptor superfamily, both VLDLR and ApoER2 have in their structure an internalization domain calledNPxYmotif.After binding to the receptors reelin is internalized byendocytosis,and the N-terminal fragment of the protein is re-secreted.[85]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.[86]

Reelin receptors are present on bothneuronsandglial cells.Furthermore,radial gliaexpress the same amount ofApoER2but being ten times less rich inVLDLR.[55]beta-1 integrin receptorson glial cells play more important role in neuronal layering than the same receptors on the migrating neuroblasts.[87]

Reelin-dependent strengthening oflong-term potentiationis caused byApoER2interaction withNMDA 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.[88]According to one study, the hippocampal reelin expression rapidly goes up when there is need to store a memory, asdemethylasesopen up the RELN gene.[89]The activation of dendrite growth by reelin is apparently conducted throughSrcfamilykinasesand is dependent upon the expression ofCrkfamily proteins,[90]consistent with the interaction of Crk and CrkL with tyrosine-phosphorylated Dab1.[91]Moreover, aCre-loxP recombinationmouse model that lacksCrkandCrkLin most neurons[92]was reported to have thereelerphenotype, indicating that Crk/CrkL lie betweenDAB1andAktin the reelin signaling chain.

Signaling cascades

[edit]

Reelin activates the signaling cascade ofNotch-1,inducing the expression ofFABP7and prompting progenitor cells to assumeradial glialphenotype.[93]In addition, corticogenesisin vivois highly dependent upon reelin being processed by embryonic neurons,[52]which are thought to secrete some as yet unidentifiedmetalloproteinasesthat free the central signal-competent part of the protein. Some other unknown proteolytic mechanisms may also play a role.[94]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.[52]It is possible that asneuroblastsreach 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.[28]

The intracellular adaptorDAB1binds to the VLDLR and ApoER2 through anNPxYmotif and is involved in transmission of Reelin signals through these lipoprotein receptors. It becomes phosphorylated bySrc[95]andFyn[96]kinases and apparently stimulates theactincytoskeleton to change its shape, affecting the proportion of integrin receptors on the cell surface, which leads to the change inadhesion.Phosphorylation of DAB1 leads to itsubiquitinationand subsequent degradation, and this explains the heightened levels of DAB1 in the absence of reelin.[97]Suchnegative feedbackis thought to be important for proper cortical lamination.[98]Activated by two antibodies, VLDLR and ApoER2 cause DAB1 phosphorylation but seemingly without the subsequent degradation and without rescuing thereelerphenotype, and this may indicate that a part of the signal is conducted independently of DAB1.[51]

Reelin stimulates the progenitor cells to differentiate into radial glia, inducing the expression of radial glial markerBLBPby affecting theNOTCH1cascade. A fragment of anillustrationfrom Keilani et al., 2008.[93]

A protein having an important role inlissencephalyand accordingly calledLIS1(PAFAH1B1), was shown to interact with the intracellular segment of VLDLR, thus reacting to the activation of reelin pathway.[77]

Complexes

[edit]

Reelin molecules have been shown[99][100]to form a large protein complex, adisulfide-linkedhomodimer.If the homodimer fails to form, efficient tyrosinephosphorylationof DAB1in vitrofails. Moreover, the two main receptors of reelin are able to form clusters[101]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.[101]In addition, reelin itself can cut the peptide bonds holding other proteins together, being aserine protease,[46]and this may affect the cellular adhesion and migration processes. Reelin signaling leads to phosphorylation ofactin-interacting proteincofilin 1at ser3; this may stabilize the actin cytoskeleton and anchor the leading processes of migrating neuroblasts, preventing their further growth.[102][103]

Interaction with Cdk5

[edit]

Cyclin-dependent kinase 5(Cdk5), a major regulator of neuronal migration and positioning, is known to phosphorylateDAB1[104][105][106]and other cytosolic targets of reelin signaling, such asTau,[107]which could be activated also via reelin-induced deactivation ofGSK3B,[108]andNUDEL,[109]associated withLis1,one of the DAB1 targets.LTPinduction by reelin in hippocampal slices fails inp35knockouts.[110]P35 is a key Cdk5 activator, and double p35/Dab1, p35/RELN, p35/ApoER2, p35/VLDLR knockouts display increased neuronal migration deficits,[110][111]indicating a synergistic action of reelin → ApoER2/VLDLR → DAB1 and p35/p39 → Cdk5 pathways in the normal corticogenesis.

Possible pathological role

[edit]

Lissencephaly

[edit]

Disruptions of the RELN gene are considered to be the cause of the rare form oflissencephalywithcerebellar hypoplasiaclassed as amicrolissencephalycalledNorman-Roberts syndrome.[112][113]The mutations disruptsplicingof the RELNmRNAtranscript, resulting in low or undetectable amounts of reelin protein. Thephenotypein these patients was characterized byhypotonia,ataxia,and developmental delay, with lack of unsupported sitting and profound mental retardation with little or no language development. Seizures andcongenital lymphedemaare also present. A novelchromosomal translocationcausing the syndrome was described in 2007.[114]

Schizophrenia

[edit]

Reduced expression of reelin and itsmRNAlevels in the brains ofschizophreniasufferers had been reported in 1998[115]and 2000,[116]and independently confirmed in postmortem studies of the hippocampus,[12]cerebellum,[117]basal ganglia,[118]and cerebral cortex.[119][120]The reduction may reach up to 50% in some brain regions and is coupled with reduced expression ofGAD-67enzyme,[117]which catalyses the transition ofglutamatetoGABA.Blood levelsof reelin and itsisoformsare also altered in schizophrenia, along withmood disorders,according to one study.[121]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.[122]

Epigenetichypermethylation of DNA in schizophrenia patients is proposed as a cause of the reduction,[123][124]in agreement with the observations dating from the 1960s that administration ofmethionineto schizophrenic patients results in a profound exacerbation of schizophrenia symptoms in sixty to seventy percent of patients.[125][126][127][128]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;E. Costa).[13][129]A postmortem study comparing aDNA methyltransferase(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.[130]There is evidence that the change is selective, and DNMT1 is overexpressed in reelin-secreting GABAergic neurons but not in their glutamatergic neighbours.[131][132]Methylationinhibitors andhistone deacetylaseinhibitors, such asvalproic acid,increase reelin mRNA levels,[133][134][135]while L-methionine treatment downregulates the phenotypic expression of reelin.[136]

One study indicated the upregulation of histone deacetylase HDAC1 in the hippocampi of patients.[137]Histone deacetylases suppress gene promoters; hyperacetylation of histones was shown in murine models to demethylate the promoters of both reelin and GAD67.[138]DNMT1 inhibitors in animals have been shown to increase the expression of both reelin and GAD67,[139]and both DNMT inhibitors and HDAC inhibitors shown in one study[140]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.[141]SAM, being a methyl group donor necessary for DNMT activity, could further shift epigenetic control of gene expression.[citation needed]

Chromosome region7q22that harbours theRELNgene is associated with schizophrenia,[142]and the gene itself was associated with the disease in a large study that found the polymorphismrs7341475to increase the risk of the disease in women, but not in men. The women that have thesingle-nucleotide polymorphism(SNP) are about 1.4 times more likely to get ill, according to the study.[143]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.[142]The association with working memory was later replicated.[144]In one small study, nonsynonymous polymorphismVal997Leuof the gene was associated with left and right ventricular enlargement in patients.[145]

One study showed that patients have decreased levels of one of reelin receptors,VLDLR,in the peripherallymphocytes.[146]After six months ofantipsychotictherapy the expression went up; according to authors, peripheral VLRLR levels may serve as a reliable peripheral biomarker of schizophrenia.[146]

Considering the role of reelin in promoting dendritogenesis,[9][90]suggestions were made that the localized dendritic spine deficit observed in schizophrenia[147][148]could be in part connected with the downregulation of reelin.[149][150]

Reelin pathway could also be linked to schizophrenia and other psychotic disorders through its interaction with risk genes. One example is the neuronal transcription factorNPAS3,disruption of which is linked to schizophrenia[151]and learning disability. Knockout mice lacking NPAS3 or the similar proteinNPAS1have significantly lower levels of reelin;[152]the precise mechanism behind this is unknown. Another example is the schizophrenia-linked geneMTHFR,with murine knockouts showing decreased levels of reelin in the cerebellum.[153]Along the same line, it is worth noting that the gene coding for the subunitNR2Bthat is presumably affected by reelin in the process of NR2B->NR2A developmental change of NMDA receptor composition,[65]stands as one of the strongest riskgene candidates.[154]Another shared aspect between NR2B and RELN is that they both can be regulated by theTBR1transcription factor.[155]

Theheterozygousreeler mouse, which ishaploinsufficientfor the RELN gene, shares several neurochemical and behavioral abnormalities with schizophrenia and bipolar disorder,[156]but the exact relevance of these murine behavioral changes to the pathophysiology of schizophrenia remains debatable.[157]

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[158][159]and changes togene regulatory networksthat controlcell migration[160][161]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 thenasalbiopsiesof schizophrenia patients, and compared to cells from healthy controls.[160]Schizophrenia patient-derived cells have reduced levels of reelin mRNA[160]and protein[162]when compared to healthy control cells, but expresses the key reelin receptors and DAB1 accessory protein.[162]When grownin vitro,schizophrenia patient-derived cells were unable to respond to reelin coated ontotissue culturesurfaces; In contrast, cells derived from healthy controls were able to alter their cell migration when exposed to reelin.[162]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 enoughfocal adhesionsof the appropriate size when in contact with extracellular reelin.[162]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

[edit]

Decrease in RELN expression with concurrent upregulation ofDNMT1is typical ofbipolar disorderwith psychosis, but is not characteristic of patients with major depression without psychosis, which could speak of specific association of the change with psychoses.[116]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.[118]

In a genetic study conducted in 2009, preliminary evidence requiring furtherDNA replicationsuggested that variation of the RELNgene(SNPrs362719) may be associated with susceptibility tobipolar disorderin women.[163]

Autism

[edit]
Main article:Heritability of autism

Autismis aneurodevelopmental disorderthat 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.[164]

Reelin was originally in 2001 implicated in a study finding associations between autism and apolymorphicGGC/CGGrepeatpreceding 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.[165]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 largerreelinalleles were found to be transmitted more frequently than expected to affected children.[166]An additional study examining 158 subjects with German lineage likewise found no evidence of triplet repeat polymorphisms associated with autism.[167]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.[168] In 2010 a large study using data from 4 European cohorts would find some evidence for an association between autism and thers362780RELN polymorphism.[169]

Studies oftransgenicmice have been suggestive of an association, but not definitive.[170]

Temporal lobe epilepsy: granule cell dispersion

[edit]

Decreased reelin expression in the hippocampal tissue samples from patients withtemporal lobe epilepsywas found to be directly correlated with the extent ofgranule celldispersion (GCD), a major feature of the disease that is noted in 45%–73% of patients.[171][172]The dispersion, according to a small study, is associated with the RELN promoter hypermethylation.[173]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.[174]Moreover, in akainate-induced mouse epilepsy model, exogenous reelin had prevented GCD, according to one study.[175]

Alzheimer's disease

[edit]

The Reelin receptorsApoER2andVLDLRbelong to theLDLreceptor gene family.[176]All members of this family are receptors forApolipoprotein 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.ApoE4is the primary genetic risk factor for late-onsetAlzheimer'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.[176][177]According to one study, reelin expression andglycosylationpatterns are altered inAlzheimer'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.[178]This finding is in agreement with an earlier study showing the presence of Reelin associated with amyloid plaques in a transgenic AD mouse model.[179]A large genetic study of 2008 showed that RELN gene variation is associated with an increased risk of Alzheimer's disease in women.[180]The number of reelin-producing Cajal-Retzius cells is significantly decreased in the first cortical layer of patients.[181][182]Reelin has been shown to interact withamyloid precursor protein,[183]and, according to one in-vitro study, is able to counteract the Aβ-induced dampening ofNMDA-receptoractivity.[184]This is modulated by ApoE isoforms, which selectively alter the recycling of ApoER2 as well as AMPA and NMDA receptors.[185]

Cancer

[edit]

DNA methylationpatterns are often changed in tumours, and the RELN gene could be affected: according to one study, in thepancreatic cancerthe expression is suppressed, along with other reelin pathway components[186]In the same study, cutting the reelin pathway in cancer cells that still expressed reelin resulted in increased motility and invasiveness. On the contrary, inprostate cancerthe RELN expression is excessive and correlates withGleason score.[187]Retinoblastomapresents another example of RELN overexpression.[188]This gene has also been seen recurrently mutated in cases ofacute lymphoblastic leukaemia.[189]

Other conditions

[edit]

Onegenome-wide association studyindicates a possible role for RELN gene variation inotosclerosis,an abnormal growth of bone of themiddle ear.[190]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 andDAB1and speculated on possible protective effects of such over-expression.[191]In 2020, a study reported a novel variant inRELNgene (S2486G) which was associated withankylosing spondylitisin 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.[192]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.[193]

Factors affecting reelin expression

[edit]
Increased cortical reelin expression in the pups of "High LG" (licking and grooming) rats. A figure from Smit-Righter et al., 2009[194]

The expression of reelin is controlled by a number of factors besides the sheer number of Cajal-Retzius cells. For example,TBR1transcription factor regulates RELN along with otherT-element-containing genes.[155]On a higher level, increased maternal care was found to correlate with reelin expression in rat pups; such correlation was reported in hippocampus[195]and in the cortex.[194]According to one report, prolonged exposure tocorticosteronesignificantly decreased reelin expression in murine hippocampi, a finding possibly pertinent to the hypothetical role ofcorticosteroidsindepression.[196]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.[197]

Psychotropic medication

[edit]

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.[198]

According to the epigenetic hypothesis, drugs that shift the balance in favour ofdemethylationhave 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.[199]Valproic acid,ahistone 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]

Fatemi et al. conducted the study in which RELN mRNA and reelin protein levels were measured in rat prefrontal cortex following a 21-day ofintraperitoneal injectionsof the following drugs:[28]

Reelin expression Clozapine Fluoxetine Haloperidol Lithium Olanzapine 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 ofGAD65andGAD67.[200]

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