# Reelin

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Large secreted extracellular matrix glycoprotein involved in neuronal migration

RELN Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2ddu, 2e26, 2DDU, 2E26, 3A7Q Identifiers Aliases RELN, LIS2, PRO1598, RL, reelin, ETL7 External IDs OMIM: 600514; MGI: 103022; HomoloGene: 3699; GeneCards: RELN; OMA:RELN - orthologs Gene location (Human) Chr. Chromosome 7 (human)[1] Band 7q22.1 Start 103,471,381 bp[1] End 103,989,658 bp[1] Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5 A3|5 9.98 cM Start 22,089,452 bp[2] End 22,549,700 bp[2] RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in olfactory bulb cerebellar vermis cerebellar hemisphere paraflocculus of cerebellum right hemisphere of cerebellum spinal ganglia trigeminal ganglion endothelial cell tibial nerve pons Top expressed in ciliary body cerebellar vermis lobe of cerebellum iris olfactory bulb sciatic nerve endothelial cell of lymphatic vessel superior colliculus paraventricular nucleus of hypothalamus piriform cortex More reference expression data BioGPS More reference expression data Gene ontology Molecular function metal ion binding peptidase activity hydrolase activity serine-type peptidase activity lipoprotein particle receptor binding very-low-density lipoprotein particle receptor binding Cellular component cytoplasm dendrite plasma membrane extracellular region extracellular space membrane extracellular matrix neuron projection Biological process NMDA glutamate receptor clustering positive regulation of lateral motor column neuron migration dendrite development proteolysis cerebral cortex development lateral motor column neuron migration positive regulation of phosphatidylinositol 3-kinase signaling positive regulation of TOR signaling long-term memory multicellular organism development receptor localization to synapse postsynaptic density protein 95 clustering ventral spinal cord development protein localization to synapse forebrain development long-term potentiation regulation of gene expression layer formation in cerebral cortex cell migration learning associative learning cell adhesion hippocampus development spinal cord patterning cerebral cortex tangential migration positive regulation of peptidyl-tyrosine phosphorylation glial cell differentiation peptidyl-tyrosine phosphorylation positive regulation of excitatory postsynaptic potential positive regulation of CREB transcription factor activity positive regulation of protein kinase activity modulation of chemical synaptic transmission positive regulation of AMPA receptor activity brain development central nervous system development response to pain positive regulation of synapse maturation positive regulation of long-term synaptic potentiation cell morphogenesis involved in differentiation neuron migration positive regulation of neuron projection development positive regulation of small GTPase mediated signal transduction positive regulation of synaptic transmission, glutamatergic regulation of behavior positive regulation of dendritic spine morphogenesis reelin-mediated signaling pathway regulation of NMDA receptor activity positive regulation of protein tyrosine kinase activity axon guidance Sources:Amigo / QuickGO Orthologs Species Human Mouse 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 Mb Chr 5: 22.09 – 22.55 Mb PubMed search [3] [4] Wikidata View/Edit Human View/Edit Mouse

**Reelin**, encoded by the ***RELN*** gene,[5] is a large secreted [extracellular matrix](/source/Extracellular_matrix) [glycoprotein](/source/Glycoprotein) that helps regulate processes of [neuronal migration](/source/Neuronal_migration) and positioning in the developing brain by controlling [cell–cell interactions](/source/Cell%E2%80%93cell_interactions). Besides this important role in early [development](/source/Developmental_biology), reelin continues to work in the adult brain.[6] It modulates [synaptic plasticity](/source/Synaptic_plasticity) by enhancing the induction and maintenance of [long-term potentiation](/source/Long-term_potentiation).[7][8] It also stimulates dendrite and [dendritic spine](/source/Dendritic_spine) development in the [hippocampus](/source/Hippocampus),[9][10] and regulates the continuing migration of [neuroblasts](/source/Neuroblast) generated in [adult neurogenesis](/source/Adult_neurogenesis) sites of the [subventricular](/source/Subventricular_zone) and [subgranular zones](/source/Subgranular_zone). It is found not only in the [brain](/source/Brain) but also in the [liver](/source/Liver), [thyroid gland](/source/Thyroid), [adrenal gland](/source/Adrenal_gland), [fallopian tube](/source/Fallopian_tube), [breast](/source/Breast) and 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 in [schizophrenia](/source/Schizophrenia) and psychotic [bipolar disorder](/source/Bipolar_disorder),[12] but the cause of this observation remains uncertain, as studies show that [psychotropic medication itself affects reelin expression](#Psychotropic_medication). Moreover, [epigenetic](/source/Epigenetics) hypotheses aimed at explaining the changed levels of reelin expression[13] are controversial.[14][15] Total lack of reelin causes a form of [lissencephaly](/source/Lissencephaly). Reelin may also play a role in [Alzheimer's disease](/source/Alzheimer's_disease),[16] [temporal lobe epilepsy](/source/Temporal_lobe_epilepsy) and [autism](/source/Autism).

Reelin's name comes from the abnormal reeling [gait](/source/Gait) of *[reeler](/source/Reeler)* mice,[17] which were later found to have a deficiency of this brain [protein](/source/Protein) and were [homozygous](/source/Zygosity) 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](/source/Central_nervous_system) (CNS). The mice [heterozygous](/source/Zygosity) for the reelin gene, while having little neuroanatomical defects, display the [endophenotypic](/source/Endophenotype) traits linked to psychotic disorders.[18]

## Discovery

Video: the reeler mice mutants, first described in 1951 by [D.S.Falconer](/source/D.S.Falconer), were later found to lack reelin protein.

Normal and [reeler](/source/Reeler) mice brain slices.

Mutant mice have provided insight into the underlying molecular mechanisms of the development of the [central nervous system](/source/Central_nervous_system). Useful spontaneous mutations were first identified by scientists who were interested in [motor behavior](/source/Motor_behavior), and it proved relatively easy to screen [littermates](/source/Littermate) 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](https://en.wikipedia.org/wiki/Wikipedia:Citation_needed)*]

The "[reeler](/source/Reeler)" mouse was described for the first time in 1951 by [D.S.Falconer](/source/Douglas_Scott_Falconer) in [Edinburgh University](/source/Edinburgh_University) as a spontaneous variant arising in a colony of at least mildly inbred snowy-white bellied mice stock in 1948.[17] [Histopathological](/source/Histopathology) studies in the 1960s revealed that the [cerebellum](/source/Cerebellum) of 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 new [allele](/source/Allele) of reeler was obtained by means of insertional [mutagenesis](/source/Mutagenesis).[21] This provided the first [molecular marker](/source/Molecular_marker) of the [locus](/source/Locus_(genetics)), permitting the RELN gene to be mapped to chromosome 7q22 and subsequently cloned and identified.[22] Japanese scientists at [Kochi Medical School](https://en.wikipedia.org/w/index.php?title=Kochi_Medical_School&action=edit&redlink=1) successfully raised antibodies against normal brain extracts in reeler mice, later these antibodies were found to be specific [monoclonal antibodies](/source/Monoclonal_antibodies) for reelin, and were termed CR-50 (Cajal-Retzius marker 50).[23] They noted that CR-50 reacted specifically with [Cajal-Retzius neurons](/source/Cajal-Retzius_cell), whose functional role was unknown until then.[*[citation needed](https://en.wikipedia.org/wiki/Wikipedia:Citation_needed)*]

The Reelin receptors, [apolipoprotein E receptor 2](/source/ApoER2) (ApoER2) and [very-low-density lipoprotein receptor](/source/VLDLR) (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 double [knockout](/source/Gene_knockout) mice for ApoER2 and VLDLR, which both interact with Dab1, had cortical layering defects similar to those in reeler.[25]

The [downstream](/source/Upstream_and_downstream_(transduction)) [pathway](/source/Neural_pathway) of reelin was further clarified with the help of other mutant mice, including [yotari](/source/Yotari) and [scrambler](/source/Scrambler_mouse). 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](/source/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 the [DAB1](/source/DAB1) as a pivotal regulator of the reelin signaling cascade started the tedious process of deciphering its complex interactions.[*[citation needed](https://en.wikipedia.org/wiki/Wikipedia: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

Studies show that reelin is absent from [synaptic vesicles](/source/Synaptic_vesicle) and is secreted via [constitutive secretory pathway](/source/Secretory_pathway), being stored in [Golgi](/source/Golgi_apparatus) secretory vesicles.[29] Reelin's release rate is not regulated by [depolarization](/source/Depolarization), but strictly depends on its synthesis rate. This relationship is similar to that reported for the secretion of other [extracellular matrix](/source/Extracellular_matrix) proteins.[*[citation needed](https://en.wikipedia.org/wiki/Wikipedia:Citation_needed)*]

During the brain development, reelin is secreted in the cortex and hippocampus by the so-called [Cajal-Retzius cells](/source/Cajal-Retzius_cell), 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 temporary [subpial granular layer](https://en.wikipedia.org/w/index.php?title=Subpial_granular_layer&action=edit&redlink=1) (SGL), which is manifested to the highest extent in human,[31] and in the hippocampal [stratum lacunosum-moleculare](https://en.wikipedia.org/w/index.php?title=Stratum_lacunosum-moleculare&action=edit&redlink=1) and the upper marginal layer of the [dentate gyrus](/source/Dentate_gyrus).

In the developing [cerebellum](/source/Cerebellum), reelin is expressed first in the external [granule cell](/source/Granule_cell) layer (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 by [GABA](/source/GABA)-ergic [interneurons](/source/Interneuron) of the cortex and glutamatergic cerebellar neurons,[33] the glutamatergic stellate cells and fan cells in the superficial [entorhinal cortex](/source/Entorhinal_cortex) that are supposed to carry a role in encoding new [episodic memories](/source/Episodic_memories),[34] and by the few extant Cajal-Retzius cells. Among GABAergic interneurons, reelin seems to be detected predominantly in those expressing [calretinin](/source/Calretinin) and [calbindin](/source/Calbindin), like [bitufted](https://en.wikipedia.org/w/index.php?title=Bitufted_neuron&action=edit&redlink=1), [horizontal](/source/Horizontal_neurons), and [Martinotti cells](/source/Martinotti_cell), but not [parvalbumin](/source/Parvalbumin)-expressing cells, like [chandelier](/source/Chandelier_cell) or [basket neurons](/source/Basket_neuron).[35][36] In the white matter, a minute proportion of [interstitial neurons](https://en.wikipedia.org/w/index.php?title=Interstitial_neuron&action=edit&redlink=1) has 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](/source/Liver), pituitary [pars intermedia](/source/Pars_intermedia), and adrenal [chromaffin cells](/source/Chromaffin_cell).[38] In the liver, reelin is localized in [hepatic stellate cells](/source/Hepatic_stellate_cell).[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 by [retinal ganglion cells](/source/Retinal_ganglion_cell) and is also found in the [endothelial layer of the cornea](/source/Corneal_endothelium).[41] Just as in the liver, its expression increases after an injury has taken place.[*[citation needed](https://en.wikipedia.org/wiki/Wikipedia:Citation_needed)*]

The protein is also produced by the [odontoblasts](/source/Odontoblast), 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 to [transduce](/source/Transduction_(physiology)) pain 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

The structure of two [murine](/source/Mouse) *reelin repeats* as revealed by [X-ray crystallography](/source/X-ray_crystallography).[45]

Reelin is composed of 3461 amino acids with a relative molecular mass of 388 [kDa](/source/Dalton_(unit)). It also has [serine protease](/source/Serine_protease) activity.[46] Murine RELN gene consists of 65 [exons](/source/Exon) spanning approximately 450 [kb](/source/Base_pair).[47] One exon, coding for only two amino acids near the protein's [C-terminus](/source/C-terminus), undergoes [alternative splicing](/source/Alternative_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 to [F-spondin](/source/Spondin_1) (the [reeler domain](/source/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](/source/Epidermal_growth_factor) motif at their center, dividing each repeat into two subrepeats, *A* (the [BNR/Asp-box repeat](/source/BNR%2FAsp-box_repeat)) and *B* (the [EGF-like domain](/source/EGF-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 Orleans [reeler](/source/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.[49]

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.[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, trigger [Dab1](/source/DAB1) [phosphorylation](/source/Phosphorylation) and mimic functions of reelin during [cortical plate](/source/Cortical_plate) development.[51] Moreover, the processing of reelin by embryonic neurons may be necessary for proper corticogenesis.[52]

## Function

As they travel through the [rostral migratory stream](/source/Rostral_migratory_stream), neuroblasts are held together, probably in part by [thrombospondin-1](/source/Thrombospondin-1)'s binding to the reelin receptors [ApoER2](/source/ApoER2) and [VLDLR](/source/VLDLR).[53] As they arrive to the destination, the groups are dispersed by reelin and cells strike out on their individual paths. A fragment of an [illustration](https://commons.wikimedia.org/wiki/Image:Rostral_migratory_stream_mouse.jpg) from 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

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](/source/Radial_glia) and 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 an [illustration](https://commons.wikimedia.org/wiki/Image:Journal.pone.0001454.g005.jpg) from 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.

Mammalian [corticogenesis](/source/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](/source/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 cells](/source/Cajal-Retzius_cell) and some cells normally destined for the second layer.[*[citation needed](https://en.wikipedia.org/wiki/Wikipedia: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 the [radial glia](/source/Radial_glia) fibers 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](https://en.wikipedia.org/wiki/Wikipedia:Citation_needed)*]

Reelin may also ensure correct neuronal positioning in the [spinal cord](/source/Spinal_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 the [glial cells](/source/Glial_cell) that are acting as their guides, converting them into individual cells that can strike out alone to find their final position.[*[citation needed](https://en.wikipedia.org/wiki/Wikipedia:Citation_needed)*]

Top: Representative image of somatic reelin immunoreactivities found in 12-day-in-vitro hippocampal neurons. Bottom: reelin immunofluorescence (red) overlaid with [MAP2](/source/MAP2) [counterstain](/source/Counterstain) (green). A fragment of an [illustration](https://commons.wikimedia.org/wiki/Image:Profile_of_intense_and_punctate_reelin_IR_during_hippocampal_maturation_journal_pone_0005505_g001.png) from Campo et al., 2009.[62]

Reelin takes part in the developmental change of [NMDA receptor](/source/NMDA_receptor) configuration, increasing mobility of [NR2B](/source/NR2B)-containing receptors and thus decreasing the time they spend at the [synapse](/source/Synapse).[63][*[dead link](https://en.wikipedia.org/wiki/Wikipedia:Link_rot)*][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

Further information: [Adult neurogenesis](/source/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](/source/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](/source/ApoER2) and [VLDLR](/source/VLDLR), and their intracellular adapter [DAB1](/source/DAB1) function independently of Reelin,[67] most likely by the influence of a newly proposed ligand, [thrombospondin-1](/source/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 neuron [dendritic spine](/source/Dendritic_spine) expression density, the branching of [dendrites](/source/Dendrite), and the expression of [long-term potentiation](/source/Long-term_potentiation)[8] as its secretion is continued diffusely by the GABAergic cortical interneurons those origin is traced to the medial [ganglionic eminence](/source/Ganglionic_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](https://en.wikipedia.org/wiki/Wikipedia:Citation_needed)*]

## Evolutionary significance

[Cajal-Retzius cells](/source/Cajal-Retzius_cell), 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 the [amniotes](/source/Amniote) into 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, [zebrafish](/source/Zebrafish) have 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 the [HAR1](/source/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](/source/Human_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

The main reelin signaling cascade (ApoER2 and VLDLR) and its interaction with [LIS1](/source/LIS1). Zhang et al., 2008[77]
 **SFK**: [Src family kinases](/source/Src_Family_Kinases).
**JIP**: [JNK-interacting protein 1](/source/MAPK8IP1)

### 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](/source/Low_density_lipoprotein_receptor_gene_family): [VLDLR](/source/VLDL_receptor) and the [ApoER2](/source/Low_density_lipoprotein_receptor-related_protein_8).[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-1 [integrin](/source/Integrin) receptor.[83] The proposal that the proto[cadherin](/source/Cadherin) CNR1 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 called [NPxY](https://en.wikipedia.org/w/index.php?title=NPxY&action=edit&redlink=1) [motif](/source/Structural_motif). After binding to the receptors reelin is internalized by [endocytosis](/source/Endocytosis), 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 both [neurons](/source/Neuron) and [glial cells](/source/Glial_cell). Furthermore, [radial glia](/source/Radial_glia) express the same amount of [ApoER2](/source/Low_density_lipoprotein_receptor-related_protein_8) but being ten times less rich in [VLDLR](/source/VLDL_receptor).[55] [beta-1 integrin receptors](/source/CD29) on glial cells play more important role in neuronal layering than the same receptors on the migrating neuroblasts.[87]

Reelin-dependent strengthening of [long-term potentiation](/source/Long-term_potentiation) is caused by [ApoER2](/source/ApoER2) interaction with [NMDA receptor](/source/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.[88] According to one study, the hippocampal reelin expression rapidly goes up when there is need to store a memory, as [demethylases](/source/Demethylase) open up the RELN gene.[89] The activation of dendrite growth by reelin is apparently conducted through [Src](/source/Src_(gene)) family [kinases](/source/Kinase) and is dependent upon the expression of [Crk](/source/CRK_(gene)) family proteins,[90] consistent with the interaction of Crk and CrkL with tyrosine-phosphorylated Dab1.[91] Moreover, a [Cre-loxP recombination](/source/Cre-Lox_recombination) mouse model that lacks [Crk](/source/CRK_(gene)) and [CrkL](/source/CRKL) in most neurons[92] was reported to have the [reeler](/source/Reeler) phenotype, indicating that Crk/CrkL lie between [DAB1](/source/DAB1) and [Akt](/source/AKT1) in the reelin signaling chain.

### Signaling cascades

Reelin activates the signaling cascade of [Notch-1](/source/NOTCH1), inducing the expression of [FABP7](/source/FABP7) and prompting progenitor cells to assume [radial glial](/source/Radial_glia) phenotype.[93] In addition, corticogenesis *in vivo* is highly dependent upon reelin being processed by embryonic neurons,[52] which are thought to secrete some as yet unidentified [metalloproteinases](/source/Metalloproteinase) that 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 as [neuroblasts](/source/Neuroblast) 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.[28]

The intracellular adaptor [DAB1](/source/DAB1) binds to the VLDLR and ApoER2 through an [NPxY](https://en.wikipedia.org/w/index.php?title=NPxY&action=edit&redlink=1) motif and is involved in transmission of Reelin signals through these lipoprotein receptors. It becomes phosphorylated by [Src](/source/Src_(gene))[95] and [Fyn](/source/FYN)[96] kinases and apparently stimulates the [actin](/source/Actin) cytoskeleton to change its shape, affecting the proportion of integrin receptors on the cell surface, which leads to the change in [adhesion](/source/Cell_adhesion). Phosphorylation of DAB1 leads to its [ubiquitination](/source/Ubiquitination) and subsequent degradation, and this explains the heightened levels of DAB1 in the absence of reelin.[97] Such [negative feedback](/source/Negative_feedback) is 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 the [reeler](/source/Reeler) phenotype, 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 marker [BLBP](/source/FABP7) by affecting the [NOTCH1](/source/NOTCH1) cascade. A fragment of an [illustration](https://commons.wikimedia.org/wiki/Image:Reelin-induced_radial_glial_phenotype_is_dependent_on_gamma-secretase_activity.jpg) from Keilani et al., 2008.[93]

A protein having an important role in [lissencephaly](/source/Lissencephaly) and accordingly called [LIS1](/source/LIS1) ([PAFAH1B1](/source/PAFAH1B1)), was shown to interact with the intracellular segment of VLDLR, thus reacting to the activation of reelin pathway.[77]

### Complexes

Reelin molecules have been shown[99][100] to form a large protein complex, a [disulfide-linked](/source/Disulfide_bond) [homodimer](/source/Homodimer). If the homodimer fails to form, efficient tyrosine [phosphorylation](/source/Phosphorylation) of DAB1 *in vitro* fails. 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 a [serine protease](/source/Serine_protease),[46] and this may affect the cellular adhesion and migration processes. Reelin signaling leads to phosphorylation of [actin](/source/Actin)-interacting protein [cofilin 1](/source/Cofilin_1) at ser3; this may stabilize the actin cytoskeleton and anchor the leading processes of migrating neuroblasts, preventing their further growth.[102][103]

### Interaction with Cdk5

[Cyclin-dependent kinase 5](/source/Cyclin-dependent_kinase_5) (Cdk5), a major regulator of neuronal migration and positioning, is known to phosphorylate [DAB1](/source/DAB1)[104][105][106] and other cytosolic targets of reelin signaling, such as [Tau](/source/Tau_protein),[107] which could be activated also via reelin-induced deactivation of [GSK3B](/source/GSK3B),[108] and [NUDEL](/source/NDEL1),[109] associated with [Lis1](/source/PAFAH1B1), one of the DAB1 targets. [LTP](/source/Long-term_potentiation) induction by reelin in hippocampal slices fails in [p35](/source/CDK5R1) knockouts.[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

### Lissencephaly

Disruptions of the RELN gene are considered to be the cause of the rare form of [lissencephaly](/source/Lissencephaly) with [cerebellar hypoplasia](/source/Cerebellar_hypoplasia) classed as a [microlissencephaly](/source/Microlissencephaly) called [Norman-Roberts syndrome](/source/Norman-Roberts_syndrome).[112][113] The mutations disrupt [splicing](/source/Splicing_(genetics)) of the RELN [mRNA](/source/Messenger_RNA) transcript, resulting in low or undetectable amounts of reelin protein. The [phenotype](/source/Phenotype) in these patients was characterized by [hypotonia](/source/Hypotonia), [ataxia](/source/Ataxia), and developmental delay, with lack of unsupported sitting and profound intellectual disability with little or no language development. Seizures and [congenital lymphedema](/source/Congenital_lymphedema) are also present. A novel [chromosomal translocation](/source/Chromosomal_translocation) causing the syndrome was described in 2007.[114]

### Schizophrenia

Reduced expression of reelin and its [mRNA](/source/Messenger_RNA) levels in the brains of [schizophrenia](/source/Schizophrenia) sufferers had been reported in 1998[115] and 2000,[116] and independently confirmed in postmortem studies of the hippocampus,[12] [cerebellum](/source/Cerebellum),[117] [basal ganglia](/source/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 of [GAD-67](/source/GAD-67) [enzyme](/source/Enzyme),[117] which catalyses the transition of [glutamate](/source/Glutamate) to [GABA](/source/GABA). [Blood levels](/source/Blood_test) of reelin and its [isoforms](/source/Isoform) are also altered in schizophrenia, along with [mood disorders](/source/Mood_disorder), 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]

[Epigenetic](/source/Epigenetics) hypermethylation 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 of [methionine](/source/Methionine) to 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](/source/Erminio_Costa)).[13][129] A postmortem study comparing a [DNA methyltransferase](/source/DNA_methyltransferase) ([DNMT1](/source/DNA_methyltransferase#DNMT_1)) 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] [Methylation](/source/Methylation) inhibitors and [histone deacetylase](/source/Histone_deacetylase) inhibitors, such as [valproic acid](/source/Valproic_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](/source/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](https://en.wikipedia.org/wiki/Wikipedia:Citation_needed)*]

Chromosome region [7q22](https://en.wikipedia.org/w/index.php?title=7q22&action=edit&redlink=1) that harbours the *RELN* gene is associated with schizophrenia,[142] and the gene itself was associated with the disease in a large study that found the polymorphism [rs7341475](/source/Rs7341475) to increase the risk of the disease in women, but not in men. The women that have the [single-nucleotide polymorphism](/source/Single-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 has schizophrenia.[142] The association with working memory was later replicated.[144] In one small study, nonsynonymous polymorphism [Val997Leu](https://en.wikipedia.org/w/index.php?title=Val997Leu&action=edit&redlink=1) of 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](/source/VLDLR), in the peripheral [lymphocytes](/source/Lymphocyte).[146] After six months of [antipsychotic](/source/Antipsychotic) therapy 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 factor [NPAS3](/source/NPAS3), disruption of which is linked to schizophrenia[151] and learning disability. Knockout mice lacking NPAS3 or the similar protein [NPAS1](/source/NPAS1) have significantly lower levels of reelin;[152] the precise mechanism behind this is unknown. Another example is the schizophrenia-linked gene [MTHFR](/source/MTHFR), 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 subunit [NR2B](/source/GRIN2B) that is presumably affected by reelin in the process of NR2B->NR2A developmental change of NMDA receptor composition,[65] stands as one of the strongest risk [gene candidates](/source/Candidate_gene).[154] Another shared aspect between NR2B and RELN is that they both can be regulated by the [TBR1](/source/TBR1) transcription factor.[155]

The [heterozygous](/source/Zygosity) reeler mouse, which is [haploinsufficient](/source/Haploinsufficiency) for 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 to [gene regulatory networks](/source/Gene_regulatory_network) that control [cell migration](/source/Cell_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 the [nasal](/source/Nose) [biopsies](/source/Biopsy) of 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 grown *[in vitro](/source/In_vitro)*, schizophrenia patient-derived cells were unable to respond to reelin coated onto [tissue culture](/source/Tissue_culture) surfaces; 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 enough [focal adhesions](/source/Focal_adhesion) of 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

Decrease in RELN expression with concurrent upregulation of [DNMT1](/source/DNMT1) is typical of [bipolar disorder](/source/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.[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 further [DNA replication](/source/DNA_replication) suggested that variation of the RELN [gene](/source/Gene) (SNP [rs362719](https://en.wikipedia.org/w/index.php?title=Rs362719&action=edit&redlink=1)) may be associated with susceptibility to [bipolar disorder](/source/Bipolar_disorder) in women.[163]

### Autism

Main article: [Heritability of autism](/source/Heritability_of_autism)

[Autism](/source/Autism) is a [neurodevelopmental disorder](/source/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.[164]

Reelin was originally in 2001 implicated in a study finding associations between autism and a [polymorphic](/source/Polymorphism_(biology)) GGC/CGG [repeat](/source/Repeated_sequence_(DNA)) 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.[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 larger *reelin* alleles 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 the [rs362780](https://en.wikipedia.org/w/index.php?title=Rs362780&action=edit&redlink=1) RELN polymorphism.[169]

Studies of [transgenic](/source/Genetically_modified_organism) mice have been suggestive of an association, but not definitive.[170]

### Temporal lobe epilepsy: granule cell dispersion

Decreased reelin expression in the hippocampal tissue samples from patients with [temporal lobe epilepsy](/source/Temporal_lobe_epilepsy) was found to be directly correlated with the extent of [granule cell](/source/Granule_cell) dispersion (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 a [kainate](/source/Kainate)-induced mouse epilepsy model, exogenous reelin had prevented GCD, according to one study.[175]

### Alzheimer's disease

The Reelin receptors [ApoER2](/source/ApoER2) and [VLDLR](/source/VLDLR) belong to the [LDL](/source/LDL) receptor gene family.[176] All members of this family are receptors for [Apolipoprotein E](/source/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](/source/ApoE4) is the primary genetic risk factor for late-onset [Alzheimer's disease](/source/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.[176][177] According to one study, reelin expression and [glycosylation](/source/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.[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 with [amyloid precursor protein](/source/Amyloid_precursor_protein),[183] and, according to one in-vitro study, is able to counteract the Aβ-induced dampening of [NMDA-receptor](/source/NMDA-receptor) activity.[184] This is modulated by ApoE isoforms, which selectively alter the recycling of ApoER2 as well as AMPA and NMDA receptors.[185]

### Cancer

[DNA methylation](/source/DNA_methylation) patterns are often changed in tumours, and the RELN gene could be affected: according to one study, in the [pancreatic cancer](/source/Pancreatic_cancer) the 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, in [prostate cancer](/source/Prostate_cancer) the RELN expression is excessive and correlates with [Gleason score](/source/Gleason_score).[187] [Retinoblastoma](/source/Retinoblastoma) presents another example of RELN overexpression.[188] This gene has also been seen recurrently mutated in cases of [acute lymphoblastic leukaemia](/source/Acute_lymphoblastic_leukaemia).[189]

### Other conditions

One [genome-wide association study](/source/Genome-wide_association_study) indicates a possible role for RELN gene variation in [otosclerosis](/source/Otosclerosis), an abnormal growth of bone of the [middle ear](/source/Middle_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 and [DAB1](/source/DAB1) and speculated on possible protective effects of such over-expression.[191] In 2020, a study reported a novel variant in *RELN* gene (S2486G) which was associated with [ankylosing spondylitis](/source/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.[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

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, [TBR1](/source/TBR1) transcription factor regulates RELN along with other [T-element](https://en.wikipedia.org/w/index.php?title=T-element&action=edit&redlink=1)-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 to [corticosterone](/source/Corticosterone) significantly decreased reelin expression in murine hippocampi, a finding possibly pertinent to the hypothetical role of [corticosteroids](/source/Corticosteroids) in [depression](/source/Clinical_depression).[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

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 of [demethylation](/source/Demethylation) have a potential to alleviate the proposed methylation-caused downregulation of RELN and GAD67. In one study, [clozapine](/source/Clozapine) and [sulpiride](/source/Sulpiride) but not [haloperidol](/source/Haloperidol) and [olanzapine](/source/Olanzapine) were shown to increase the demethylation of both genes in mice pretreated with l-methionine.[199] [Valproic acid](/source/Valproic_acid), a [histone deacetylase inhibitor](/source/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](https://en.wikipedia.org/wiki/Wikipedia: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 of [intraperitoneal injections](/source/Intraperitoneal_injection) of 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](/source/VLDLR), [DAB1](/source/DAB1), [GSK3B](/source/GSK3B)) of the signaling chain was measured besides reelin itself, and also the expression of [GAD65](/source/GAD65) and [GAD67](/source/GAD67).[200]

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1. **[^](#cite_ref-reelin_G_scholar_search_title_27-0)** ["Reelin" mentioned in the titles of scientific literature](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) – a search in the [Google Scholar](/source/Google_Scholar)

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1. **[^](#cite_ref-No_parvalbumin_1999_36-0)** Pesold C, Liu WS, Guidotti A, Costa E, Caruncho HJ (March 1999). ["Cortical bitufted, horizontal, and Martinotti cells preferentially express and secrete reelin into perineuronal nets, nonsynaptically modulating gene expression"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC15922). *Proceedings of the National Academy of Sciences of the United States of America*. **96** (6): 3217–22. [Bibcode](/source/Bibcode_(identifier)):[1999PNAS...96.3217P](https://ui.adsabs.harvard.edu/abs/1999PNAS...96.3217P). [doi](/source/Doi_(identifier)):[10.1073/pnas.96.6.3217](https://doi.org/10.1073%2Fpnas.96.6.3217). [PMC](/source/PMC_(identifier)) [15922](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC15922). [PMID](/source/PMID_(identifier)) [10077664](https://pubmed.ncbi.nlm.nih.gov/10077664).

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1. **[^](#cite_ref-bodyexpr_38-0)** Smalheiser NR, Costa E, Guidotti A, Impagnatiello F, Auta J, Lacor P, et al. (February 2000). ["Expression of reelin in adult mammalian blood, liver, pituitary pars intermedia, and adrenal chromaffin cells"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC15597). *Proceedings of the National Academy of Sciences of the United States of America*. **97** (3): 1281–6. [Bibcode](/source/Bibcode_(identifier)):[2000PNAS...97.1281S](https://ui.adsabs.harvard.edu/abs/2000PNAS...97.1281S). [doi](/source/Doi_(identifier)):[10.1073/pnas.97.3.1281](https://doi.org/10.1073%2Fpnas.97.3.1281). [PMC](/source/PMC_(identifier)) [15597](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC15597). [PMID](/source/PMID_(identifier)) [10655522](https://pubmed.ncbi.nlm.nih.gov/10655522).

1. **[^](#cite_ref-liver2_39-0)** Samama B, Boehm N (July 2005). ["Reelin immunoreactivity in lymphatics and liver during development and adult life"](https://doi.org/10.1002%2Far.a.20202). *The Anatomical Record Part A: Discoveries in Molecular, Cellular, and Evolutionary Biology*. **285** (1): 595–9. [doi](/source/Doi_(identifier)):[10.1002/ar.a.20202](https://doi.org/10.1002%2Far.a.20202). [PMID](/source/PMID_(identifier)) [15912522](https://pubmed.ncbi.nlm.nih.gov/15912522).

1. ^ [***a***](#cite_ref-Kobold_2002_liver1_40-0) [***b***](#cite_ref-Kobold_2002_liver1_40-1) Kobold D, Grundmann A, Piscaglia F, Eisenbach C, Neubauer K, Steffgen J, et al. (May 2002). "Expression of reelin in hepatic stellate cells and during hepatic tissue repair: a novel marker for the differentiation of HSC from other liver myofibroblasts". *Journal of Hepatology*. **36** (5): 607–13. [doi](/source/Doi_(identifier)):[10.1016/S0168-8278(02)00050-8](https://doi.org/10.1016%2FS0168-8278%2802%2900050-8). [PMID](/source/PMID_(identifier)) [11983443](https://pubmed.ncbi.nlm.nih.gov/11983443).

1. ^ [***a***](#cite_ref-pmid17120005_41-0) [***b***](#cite_ref-pmid17120005_41-1) Pulido JS, Sugaya I, Comstock J, Sugaya K (June 2007). "Reelin expression is upregulated following ocular tissue injury". *Graefe's Archive for Clinical and Experimental Ophthalmology*. **245** (6): 889–93. [doi](/source/Doi_(identifier)):[10.1007/s00417-006-0458-4](https://doi.org/10.1007%2Fs00417-006-0458-4). [PMID](/source/PMID_(identifier)) [17120005](https://pubmed.ncbi.nlm.nih.gov/17120005). [S2CID](/source/S2CID_(identifier)) [12397364](https://api.semanticscholar.org/CorpusID:12397364).

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1. ^ [***a***](#cite_ref-pmid11252768_176-0) [***b***](#cite_ref-pmid11252768_176-1) Herz J, Beffert U (October 2000). "Apolipoprotein E receptors: linking brain development and Alzheimer's disease". *Nature Reviews. Neuroscience*. **1** (1): 51–8. [doi](/source/Doi_(identifier)):[10.1038/35036221](https://doi.org/10.1038%2F35036221). [PMID](/source/PMID_(identifier)) [11252768](https://pubmed.ncbi.nlm.nih.gov/11252768). [S2CID](/source/S2CID_(identifier)) [27105032](https://api.semanticscholar.org/CorpusID:27105032).

1. **[^](#cite_ref-pmid17053810_177-0)** Herz J, Chen Y (November 2006). "Reelin, lipoprotein receptors and synaptic plasticity". *Nature Reviews. Neuroscience*. **7** (11): 850–9. [doi](/source/Doi_(identifier)):[10.1038/nrn2009](https://doi.org/10.1038%2Fnrn2009). [PMID](/source/PMID_(identifier)) [17053810](https://pubmed.ncbi.nlm.nih.gov/17053810). [S2CID](/source/S2CID_(identifier)) [44317115](https://api.semanticscholar.org/CorpusID:44317115).

1. **[^](#cite_ref-alz_178-0)** Botella-López A, Burgaya F, Gavín R, García-Ayllón MS, Gómez-Tortosa E, Peña-Casanova J, et al. (April 2006). ["Reelin expression and glycosylation patterns are altered in Alzheimer's disease"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1414634). *Proceedings of the National Academy of Sciences of the United States of America*. **103** (14): 5573–8. [Bibcode](/source/Bibcode_(identifier)):[2006PNAS..103.5573B](https://ui.adsabs.harvard.edu/abs/2006PNAS..103.5573B). [doi](/source/Doi_(identifier)):[10.1073/pnas.0601279103](https://doi.org/10.1073%2Fpnas.0601279103). [PMC](/source/PMC_(identifier)) [1414634](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1414634). [PMID](/source/PMID_(identifier)) [16567613](https://pubmed.ncbi.nlm.nih.gov/16567613).

1. **[^](#cite_ref-alzmouse_179-0)** Wirths O, Multhaup G, Czech C, Blanchard V, Tremp G, Pradier L, et al. (December 2001). "Reelin in plaques of beta-amyloid precursor protein and presenilin-1 double-transgenic mice". *Neuroscience Letters*. **316** (3): 145–8. [doi](/source/Doi_(identifier)):[10.1016/S0304-3940(01)02399-0](https://doi.org/10.1016%2FS0304-3940%2801%2902399-0). [PMID](/source/PMID_(identifier)) [11744223](https://pubmed.ncbi.nlm.nih.gov/11744223). [S2CID](/source/S2CID_(identifier)) [35475092](https://api.semanticscholar.org/CorpusID:35475092).

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1. **[^](#cite_ref-pmid16051543_181-0)** Baloyannis SJ (July 2005). "Morphological and morphometric alterations of Cajal-Retzius cells in early cases of Alzheimer's disease: a Golgi and electron microscope study". *The International Journal of Neuroscience*. **115** (7): 965–80. [doi](/source/Doi_(identifier)):[10.1080/00207450590901396](https://doi.org/10.1080%2F00207450590901396). [PMID](/source/PMID_(identifier)) [16051543](https://pubmed.ncbi.nlm.nih.gov/16051543). [S2CID](/source/S2CID_(identifier)) [36197073](https://api.semanticscholar.org/CorpusID:36197073).

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1. **[^](#cite_ref-pmid19515914_183-0)** Hoe HS, Lee KJ, Carney RS, Lee J, Markova A, Lee JY, et al. (June 2009). ["Interaction of reelin with amyloid precursor protein promotes neurite outgrowth"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2759694). *The Journal of Neuroscience*. **29** (23): 7459–73. [doi](/source/Doi_(identifier)):[10.1523/JNEUROSCI.4872-08.2009](https://doi.org/10.1523%2FJNEUROSCI.4872-08.2009). [PMC](/source/PMC_(identifier)) [2759694](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2759694). [PMID](/source/PMID_(identifier)) [19515914](https://pubmed.ncbi.nlm.nih.gov/19515914).

1. **[^](#cite_ref-Herz2009relnabeta_184-0)** Durakoglugil MS, Chen Y, White CL, Kavalali ET, Herz J (September 2009). ["Reelin signaling antagonizes beta-amyloid at the synapse"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747222). *Proceedings of the National Academy of Sciences of the United States of America*. **106** (37): 15938–43. [Bibcode](/source/Bibcode_(identifier)):[2009PNAS..10615938D](https://ui.adsabs.harvard.edu/abs/2009PNAS..10615938D). [doi](/source/Doi_(identifier)):[10.1073/pnas.0908176106](https://doi.org/10.1073%2Fpnas.0908176106). [PMC](/source/PMC_(identifier)) [2747222](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747222). [PMID](/source/PMID_(identifier)) [19805234](https://pubmed.ncbi.nlm.nih.gov/19805234).

1. **[^](#cite_ref-pmid20547867_185-0)** Chen Y, Durakoglugil MS, Xian X, Herz J (June 2010). ["ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2900641). *Proceedings of the National Academy of Sciences of the United States of America*. **107** (26): 12011–6. [Bibcode](/source/Bibcode_(identifier)):[2010PNAS..10712011C](https://ui.adsabs.harvard.edu/abs/2010PNAS..10712011C). [doi](/source/Doi_(identifier)):[10.1073/pnas.0914984107](https://doi.org/10.1073%2Fpnas.0914984107). [PMC](/source/PMC_(identifier)) [2900641](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2900641). [PMID](/source/PMID_(identifier)) [20547867](https://pubmed.ncbi.nlm.nih.gov/20547867).

1. **[^](#cite_ref-Pancreatic_Cancer_2006_186-0)** Sato N, Fukushima N, Chang R, Matsubayashi H, Goggins M (February 2006). ["Differential and epigenetic gene expression profiling identifies frequent disruption of the RELN pathway in pancreatic cancers"](https://doi.org/10.1053%2Fj.gastro.2005.11.008). *Gastroenterology*. **130** (2): 548–65. [doi](/source/Doi_(identifier)):[10.1053/j.gastro.2005.11.008](https://doi.org/10.1053%2Fj.gastro.2005.11.008). [PMID](/source/PMID_(identifier)) [16472607](https://pubmed.ncbi.nlm.nih.gov/16472607).

1. **[^](#cite_ref-Prostate_Cancer_2007_1_187-0)** Perrone G, Vincenzi B, Zagami M, Santini D, Panteri R, Flammia G, et al. (March 2007). ["Reelin expression in human prostate cancer: a marker of tumor aggressiveness based on correlation with grade"](https://doi.org/10.1038%2Fmodpathol.3800743). *Modern Pathology*. **20** (3): 344–51. [doi](/source/Doi_(identifier)):[10.1038/modpathol.3800743](https://doi.org/10.1038%2Fmodpathol.3800743). [PMID](/source/PMID_(identifier)) [17277764](https://pubmed.ncbi.nlm.nih.gov/17277764).

1. **[^](#cite_ref-pmid17615543_188-0)** Seigel GM, Hackam AS, Ganguly A, Mandell LM, Gonzalez-Fernandez F (June 2007). ["Human embryonic and neuronal stem cell markers in retinoblastoma"](http://www.molvis.org/molvis/v13/a90/). *Molecular Vision*. **13**: 823–32. [PMC](/source/PMC_(identifier)) [2768758](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768758). [PMID](/source/PMID_(identifier)) [17615543](https://pubmed.ncbi.nlm.nih.gov/17615543).

1. **[^](#cite_ref-doi.10.1038/nature10725_189-0)** Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D, et al. (January 2012). ["The genetic basis of early T-cell precursor acute lymphoblastic leukaemia"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267575). *Nature*. **481** (7380): 157–63. [Bibcode](/source/Bibcode_(identifier)):[2012Natur.481..157Z](https://ui.adsabs.harvard.edu/abs/2012Natur.481..157Z). [doi](/source/Doi_(identifier)):[10.1038/nature10725](https://doi.org/10.1038%2Fnature10725). [PMC](/source/PMC_(identifier)) [3267575](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267575). [PMID](/source/PMID_(identifier)) [22237106](https://pubmed.ncbi.nlm.nih.gov/22237106).

1. **[^](#cite_ref-pmid19230858_190-0)** Schrauwen I, Ealy M, Huentelman MJ, Thys M, Homer N, Vanderstraeten K, et al. (March 2009). ["A genome-wide analysis identifies genetic variants in the RELN gene associated with otosclerosis"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667982). *American Journal of Human Genetics*. **84** (3): 328–38. [doi](/source/Doi_(identifier)):[10.1016/j.ajhg.2009.01.023](https://doi.org/10.1016%2Fj.ajhg.2009.01.023). [PMC](/source/PMC_(identifier)) [2667982](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667982). [PMID](/source/PMID_(identifier)) [19230858](https://pubmed.ncbi.nlm.nih.gov/19230858).

1. **[^](#cite_ref-pmid18062806_191-0)** Delahaye NF, Coltel N, Puthier D, Barbier M, Benech P, Joly F, et al. (December 2007). ["Gene expression analysis reveals early changes in several molecular pathways in cerebral malaria-susceptible mice versus cerebral malaria-resistant mice"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2246131). *BMC Genomics*. **8**: 452. [doi](/source/Doi_(identifier)):[10.1186/1471-2164-8-452](https://doi.org/10.1186%2F1471-2164-8-452). [PMC](/source/PMC_(identifier)) [2246131](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2246131). [PMID](/source/PMID_(identifier)) [18062806](https://pubmed.ncbi.nlm.nih.gov/18062806).

1. **[^](#cite_ref-192)** Garshasbi M, Mahmoudi M, Razmara E, Vojdanian M, Aslani S, Farhadi E, et al. (June 2020). ["Identification of RELN variant p.(Ser2486Gly) in an Iranian family with ankylosing spondylitis; the first association of RELN and AS"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253431). *European Journal of Human Genetics*. **28** (6): 754–762. [doi](/source/Doi_(identifier)):[10.1038/s41431-020-0573-4](https://doi.org/10.1038%2Fs41431-020-0573-4). [PMC](/source/PMC_(identifier)) [7253431](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253431). [PMID](/source/PMID_(identifier)) [32001840](https://pubmed.ncbi.nlm.nih.gov/32001840).

1. **[^](#cite_ref-193)** ["'Reelin' in a New Treatment for Multiple Sclerosis"](https://neurosciencenews.com/reelin-multiple-sclerosis-16819/). 12 August 2020.

1. ^ [***a***](#cite_ref-pmid19357777_194-0) [***b***](#cite_ref-pmid19357777_194-1) Smit-Rigter LA, Champagne DL, van Hooft JA (2009). Linden R (ed.). ["Lifelong impact of variations in maternal care on dendritic structure and function of cortical layer 2/3 pyramidal neurons in rat offspring"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663818). *PLOS ONE*. **4** (4) e5167. [Bibcode](/source/Bibcode_(identifier)):[2009PLoSO...4.5167S](https://ui.adsabs.harvard.edu/abs/2009PLoSO...4.5167S). [doi](/source/Doi_(identifier)):[10.1371/journal.pone.0005167](https://doi.org/10.1371%2Fjournal.pone.0005167). [PMC](/source/PMC_(identifier)) [2663818](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663818). [PMID](/source/PMID_(identifier)) [19357777](https://pubmed.ncbi.nlm.nih.gov/19357777).

1. **[^](#cite_ref-pmid16484373_195-0)** Weaver IC, Meaney MJ, Szyf M (February 2006). ["Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1413873). *Proceedings of the National Academy of Sciences of the United States of America*. **103** (9): 3480–5. [Bibcode](/source/Bibcode_(identifier)):[2006PNAS..103.3480W](https://ui.adsabs.harvard.edu/abs/2006PNAS..103.3480W). [doi](/source/Doi_(identifier)):[10.1073/pnas.0507526103](https://doi.org/10.1073%2Fpnas.0507526103). [PMC](/source/PMC_(identifier)) [1413873](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1413873). [PMID](/source/PMID_(identifier)) [16484373](https://pubmed.ncbi.nlm.nih.gov/16484373).

1. **[^](#cite_ref-pmid19477232_196-0)** Lussier AL, Caruncho HJ, Kalynchuk LE (August 2009). "Repeated exposure to corticosterone, but not restraint, decreases the number of reelin-positive cells in the adult rat hippocampus". *Neuroscience Letters*. **460** (2): 170–4. [doi](/source/Doi_(identifier)):[10.1016/j.neulet.2009.05.050](https://doi.org/10.1016%2Fj.neulet.2009.05.050). [PMID](/source/PMID_(identifier)) [19477232](https://pubmed.ncbi.nlm.nih.gov/19477232). [S2CID](/source/S2CID_(identifier)) [5305922](https://api.semanticscholar.org/CorpusID:5305922).

1. **[^](#cite_ref-pmid19952965_197-0)** Lintas C, Persico AM (January 2010). "Neocortical RELN promoter methylation increases significantly after puberty". *NeuroReport*. **21** (2): 114–8. [doi](/source/Doi_(identifier)):[10.1097/WNR.0b013e328334b343](https://doi.org/10.1097%2FWNR.0b013e328334b343). [hdl](/source/Hdl_(identifier)):[11380/1250925](https://hdl.handle.net/11380%2F1250925). [PMID](/source/PMID_(identifier)) [19952965](https://pubmed.ncbi.nlm.nih.gov/19952965). [S2CID](/source/S2CID_(identifier)) [206137259](https://api.semanticscholar.org/CorpusID:206137259).

1. **[^](#cite_ref-198)** Ishii K, Kubo KI, Nakajima K (18 October 2016). ["Reelin and Neuropsychiatric Disorders"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067484). *Frontiers in Cellular Neuroscience*. **10**: 229. [doi](/source/Doi_(identifier)):[10.3389/fncel.2016.00229](https://doi.org/10.3389%2Ffncel.2016.00229). [PMC](/source/PMC_(identifier)) [5067484](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067484). [PMID](/source/PMID_(identifier)) [27803648](https://pubmed.ncbi.nlm.nih.gov/27803648).

1. **[^](#cite_ref-pmid18757738_199-0)** Dong E, Nelson M, Grayson DR, Costa E, Guidotti A (September 2008). ["Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2533238). *Proceedings of the National Academy of Sciences of the United States of America*. **105** (36): 13614–9. [Bibcode](/source/Bibcode_(identifier)):[2008PNAS..10513614D](https://ui.adsabs.harvard.edu/abs/2008PNAS..10513614D). [doi](/source/Doi_(identifier)):[10.1073/pnas.0805493105](https://doi.org/10.1073%2Fpnas.0805493105). [PMC](/source/PMC_(identifier)) [2533238](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2533238). [PMID](/source/PMID_(identifier)) [18757738](https://pubmed.ncbi.nlm.nih.gov/18757738).

1. **[^](#cite_ref-pmid19359144_200-0)** Fatemi SH, Reutiman TJ, Folsom TD (June 2009). "Chronic psychotropic drug treatment causes differential expression of Reelin signaling system in frontal cortex of rats". *Schizophrenia Research*. **111** (1–3): 138–52. [doi](/source/Doi_(identifier)):[10.1016/j.schres.2009.03.002](https://doi.org/10.1016%2Fj.schres.2009.03.002). [PMID](/source/PMID_(identifier)) [19359144](https://pubmed.ncbi.nlm.nih.gov/19359144). [S2CID](/source/S2CID_(identifier)) [37048872](https://api.semanticscholar.org/CorpusID:37048872).

## Further reading

Wikimedia Commons has media related to [Reelin](https://commons.wikimedia.org/wiki/Category:Reelin).

- Fatemi SH (March 2005). "Reelin glycoprotein: structure, biology and roles in health and disease". *Molecular Psychiatry*. **10** (3). Springer: 251–257. [doi](/source/Doi_(identifier)):[10.1038/sj.mp.4001613](https://doi.org/10.1038%2Fsj.mp.4001613). [ISBN](/source/ISBN_(identifier)) [978-0-387-76760-4](https://en.wikipedia.org/wiki/Special:BookSources/978-0-387-76760-4). [PMID](/source/PMID_(identifier)) [15583703](https://pubmed.ncbi.nlm.nih.gov/15583703). [S2CID](/source/S2CID_(identifier)) [21206951](https://api.semanticscholar.org/CorpusID:21206951).

- Förster E, Jossin Y, Zhao S, Chai X, Frotscher M, Goffinet AM (February 2006). "Recent progress in understanding the role of Reelin in radial neuronal migration, with specific emphasis on the dentate gyrus". *The European Journal of Neuroscience*. **23** (4): 901–9. [doi](/source/Doi_(identifier)):[10.1111/j.1460-9568.2006.04612.x](https://doi.org/10.1111%2Fj.1460-9568.2006.04612.x). [PMID](/source/PMID_(identifier)) [16519655](https://pubmed.ncbi.nlm.nih.gov/16519655). [S2CID](/source/S2CID_(identifier)) [25269492](https://api.semanticscholar.org/CorpusID:25269492).

- Beffert U, Stolt PC, Herz J (March 2004). ["Functions of lipoprotein receptors in neurons"](https://doi.org/10.1194%2Fjlr.R300017-JLR200). *Journal of Lipid Research*. **45** (3): 403–9. [doi](/source/Doi_(identifier)):[10.1194/jlr.R300017-JLR200](https://doi.org/10.1194%2Fjlr.R300017-JLR200). [PMID](/source/PMID_(identifier)) [14657206](https://pubmed.ncbi.nlm.nih.gov/14657206).

- Dong E, Agis-Balboa RC, Simonini MV, Grayson DR, Costa E, Guidotti A (August 2005). ["Reelin and glutamic acid decarboxylase67 promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1194936). *Proceedings of the National Academy of Sciences of the United States of America*. **102** (35): 12578–83. [Bibcode](/source/Bibcode_(identifier)):[2005PNAS..10212578D](https://ui.adsabs.harvard.edu/abs/2005PNAS..10212578D). [doi](/source/Doi_(identifier)):[10.1073/pnas.0505394102](https://doi.org/10.1073%2Fpnas.0505394102). [PMC](/source/PMC_(identifier)) [1194936](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1194936). [PMID](/source/PMID_(identifier)) [16113080](https://pubmed.ncbi.nlm.nih.gov/16113080).

- Magdaleno SM, Curran T (December 2001). ["Brain development: integrins and the Reelin pathway"](https://doi.org/10.1016%2FS0960-9822%2801%2900618-2). *Current Biology*. **11** (24): R1032-5. [Bibcode](/source/Bibcode_(identifier)):[2001CBio...11R1032M](https://ui.adsabs.harvard.edu/abs/2001CBio...11R1032M). [doi](/source/Doi_(identifier)):[10.1016/S0960-9822(01)00618-2](https://doi.org/10.1016%2FS0960-9822%2801%2900618-2). [PMID](/source/PMID_(identifier)) [11747842](https://pubmed.ncbi.nlm.nih.gov/11747842). [S2CID](/source/S2CID_(identifier)) [8790079](https://api.semanticscholar.org/CorpusID:8790079).

- Hong SE, Shugart YY, Huang DT, Shahwan SA, Grant PE, Hourihane JO, et al. (September 2000). "Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations". *Nature Genetics*. **26** (1): 93–6. [doi](/source/Doi_(identifier)):[10.1038/79246](https://doi.org/10.1038%2F79246). [PMID](/source/PMID_(identifier)) [10973257](https://pubmed.ncbi.nlm.nih.gov/10973257). [S2CID](/source/S2CID_(identifier)) [67748801](https://api.semanticscholar.org/CorpusID:67748801).

## External links

Look up ***[reelin](https://en.wiktionary.org/wiki/Special:Search/reelin)*** in Wiktionary, the free dictionary.

- Overview of all the structural information available in the [PDB](/source/Protein_Data_Bank) for [UniProt](/source/UniProt): *[Q60841](https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/Q60841)* (Mouse Reelin) at the [PDBe-KB](/source/PDBe-KB).

- ["Gabriella D'Arcangelo"](https://web.archive.org/web/20080725055259/http://www.lifesci.rutgers.edu/%7Emolbiosci/faculty/darcangelo.html). Rutgers University. Archived from [the original](http://lifesci.rutgers.edu/~molbiosci/faculty/darcangelo.html) on 25 July 2008. Retrieved 23 August 2008. the scientist who discovered the reelin gene and protein

- [Human RELN at WikiGenes](https://web.archive.org/web/20170919165819/https://www.wikigenes.org/e/gene/e/5649.html)

- ["Reelin gene expression in mice"](http://www.stjudebgem.org/web/view/probe/viewProbeDetails.php?id=404). *Brain Gene Expression Map*. St. Jude Children's Research Hospital. Retrieved 23 August 2008.{{[cite web](https://en.wikipedia.org/wiki/Template:Cite_web)}}: CS1 maint: deprecated archival service ([link](https://en.wikipedia.org/wiki/Category:CS1_maint:_deprecated_archival_service))

v t e PDB gallery 2ddu: Crystal structure of the third repeat domain of reelin 2e26: Crystal structure of two repeat fragment of reelin

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v t e Hydrolase: proteases (EC 3.4) 3.4.11-19: Exopeptidase 3.4.11 Aminopeptidase Alanine Arginyl Aspartyl Cystinyl Leucyl Glutamyl Methionyl 1 2 O 3.4.13 Dipeptidase 1 2 3 3.4.14 Dipeptidyl peptidase Cathepsin C Dipeptidyl peptidase-4 Tripeptidyl peptidase Tripeptidyl peptidase I Tripeptidyl peptidase II 3.4.15 Angiotensin-converting enzyme 3.4.16 Serine type carboxypeptidases: Cathepsin A DD-Transpeptidase 3.4.17 Metalloexopeptidases Carboxypeptidase A A1 A2 B C E Glutamate II Other/ungrouped Metalloexopeptidase 3.4.21-25: Endopeptidase Serine protease Cysteine protease Aspartic protease Metalloendopeptidase Threonine endopeptidase Proteasome endopeptidase complex HslU—HslV peptidase Other/ungrouped: Amyloid-beta precursor protein secretase Alpha secretase Beta-secretase 1 Beta-secretase 2 Gamma secretase 3.4.99: Unknown Staphylokinase

v t e Endopeptidases: serine proteases/serine endopeptidases (EC 3.4.21) Digestive enzymes Enteropeptidase Trypsin Chymotrypsin Elastase Neutrophil Pancreatic Coagulation factors: Thrombin Factor VIIa Factor IXa Factor Xa Factor XIa Factor XIIa Kallikrein PSA KLK1 KLK2 KLK3 KLK4 KLK5 KLK6 KLK7 KLK8 KLK9 KLK10 KLK11 KLK12 KLK13 KLK14 KLK15 fibrinolysis: Plasmin Plasminogen activator Tissue-type plasminogen activator Urinary plasminogen activator Complement system Factor B Factor D Factor I MASP MASP1 MASP2 C3-convertase Other immune system Chymase Granzyme Tryptase Proteinase 3/Myeloblastin Venombin Ancrod Batroxobin Other Acrosin Prolyl endopeptidase Pronase Proprotein convertases 1 2 Prostasin Reelin Subtilisin/Furin/S1P4 Sedolisin/TPP1 Streptokinase Cathepsin A G

v t e Enzymes Activity Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis Regulation Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator Classification EC number Enzyme superfamily Enzyme family List of enzymes Kinetics Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics Types EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

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Adapted from the Wikipedia article [Reelin](https://en.wikipedia.org/wiki/Reelin) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Reelin?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.