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Reelin
PDB rendering based on 2ddu. The Protein Data Bank ( PDB) is a repository for 3-D structural data of Proteins and Nucleic acids These data typically obtained by X-ray crystallography
Available structures: 2ddu, 2e26
Identifiers
Symbol(s) RELN; RL
External IDs OMIM: 600514 MGI: 103022 HomoloGene: 3699
RNA expression pattern

More reference expression data
Orthologs
Human Mouse
Entrez 5649 19699
Ensembl ENSG00000189056 ENSMUSG00000042453
Uniprot P78509 Q148P9
Refseq NM_005045 (mRNA)
NP_005036 (protein)		 NM_011261 (mRNA)
NP_035391 (protein)
Location Chr 7: 102.9 - 103.42 Mb Chr 5: 21.4 - 21.86 Mb
Pubmed search [2] [3]

Reelin is a protein found mainly in the brain, but also in the spinal cord, blood and other body organs and tissues. The Human Genome Organisation (HUGO is an organization involved in the Human Genome Project, a project about mapping the human genome The Mouse Genome Informatics (MGI website is run by The Jackson Laboratory. HomoloGene, a tool of the National Center for Biotechnology Information (NCBI is a system for automated detection of homologs (similarity attributable to descent The Entrez Global Query Cross-Database Search System is a powerful Federated search engine or Web portal that allows users to search many discrete Health sciences Ensembl is a joint scientific project between the European Bioinformatics Institute and the Wellcome Trust Sanger Institute, which was launched in 1999 in response to the imminent UniProt is the uni versal prot ein resource a central repository of Protein data created by combining Swiss-Prot, TrEMBL PubMed is a free search engine for accessing the MEDLINE database of citations and abstracts of biomedical research articles Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl The brain is the center of the Nervous system in animals All Vertebrates and the majority of Invertebrates have a brain Reelin is crucial for regulating the processes of neuronal migration and positioning in the developing brain. The study of neural development draws on both Neuroscience and Developmental biology to describe the cellular and molecular mechanisms by which complex Nervous Besides this important role in the early period, reelin continues to work in the adult brain. It modulates the synaptic plasticity by enhancing LTP induction and maintenance. In Neuroscience, synaptic plasticity is the ability of the connection or Synapse, between two Neurons to change in strength. In Neuroscience, long-term potentiation ( LTP) is the long-lasting improvement in communication between two Neurons that results from stimulating them [1][2] It also stimulates dendrite development[3] and regulates the continuing migration of neuroblasts generated in adult neurogenesis sites like subventricular and subgranular zones. A neuroblast is a dividing cell that will develop into Neurons or Glia. Neurogenesis ( birth of Neurons ' is the process by which neurons are created Subventricular zone ( SVZ) is a paired brain structure situated throughout the lateral walls of the Lateral ventricles. Subgranular zone ( SGZ) is a brain region in the Dentate gyrus where adult Neurogenesis occurs

Reelin is implicated in pathogenesis of several brain diseases: significantly lowered expression of the protein have been found in schizophrenia and psychotic bipolar disorder. Schizophrenia ( from the Greek roots schizein (σχίζειν "to split" and phrēn Total lack of reelin causes a form of lissencephaly; reelin also may play a role in Alzheimer's disease, temporal lobe epilepsy, and autism. Lissencephaly, which literally means smooth brain, is a rare brain formation disorder characterized by the lack of normal convolutions (folds in the brain Alzheimer's disease ( AD) also called Alzheimer disease or simply Alzheimer's, is the most common form of Dementia. Temporal lobe epilepsy is a form of focal Epilepsy, a chronic neurological condition characterized by recurrent Seizures While Language development. The terminology

Reelin's name comes from the abnormal reeling gait of reeler mice,[4] which were found to have a deficiency of this brain protein and were homozygous for the RELN gene, which encodes reelin synthesis. Key pathological findings in the Reeler brain structure Inversion of cortical layers Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl Zygosity refers to the genetic condition of a Zygote. In genetics zygosity describes the similarity or dissimilarity of DNA between Homologous The primary phenotype associated with loss of reelin function is inverted cortex, a neuroanatomical defect in which the six cortical layers are inverted. Heterozygous mice for the reelin gene have very little obvious neuroanatomical defect but those that they have resemble the changes of the human schizophrenic brain. Zygosity refers to the genetic condition of a Zygote. In genetics zygosity describes the similarity or dissimilarity of DNA between Homologous Schizophrenia ( from the Greek roots schizein (σχίζειν "to split" and phrēn


Contents

History

Normal and Reeler mice brain slices.
Normal and Reeler mice brain slices. Key pathological findings in the Reeler brain structure Inversion of cortical layers

Mutant mice provide insight into the underlying molecular mechanisms of the development of the CNS. In Vertebrates the central nervous system ( CNS) is the part of the Nervous system which is enclosed in the Meninges. These spontaneous mutations were first identified by scientists interested in motor behavior, and it proved relatively easy to screen littermates for mice that showed difficulties moving around the cage. For other meanings of litter see Litter (disambiguation. A litter is the offspring at one birth of Animals from the same mother and usually A number of such mice were found and given descriptive names such as reeler, weaver, lurcher, nervous, and staggerer.

The "reeler" mouse was first described in the 1951 edition of Journal of Genetics by Douglas Scott Falconer. Key pathological findings in the Reeler brain structure Inversion of cortical layers Year 1951 ( MCMLI) was a Common year starting on Monday. Events of 1951 January The Journal of Genetics (not to be confused with the journal " Genetics " is a Scientific journal in the field of Genetics Douglas Scott Falconer FRS FRSE ( March 10, 1913, Oldmeldrum, Aberdeenshire – February 23, 2004 [4] Histopathological studies in the 1960's revealed that the reeler cerebellum is dramatically decreased in size and the normal laminar organization found in several brain regions is disrupted. [5] 1970's brought the discovery of cellular layers inversion in the mice neocortex[6], which attracted more attention to the reeler mutation.

In 1995, the RELN gene and protein were discovered at chromosome 7q22 by Gabriella D'Arcangelo and colleagues[7]. Year 1995 ( MCMXCV) was a Common year starting on Sunday. Events of 1995 Almost immediately, Japanese scientists at Kochi Medical School had successfully created the first monoclonal antibody for reelin, called CR-50. Monoclonal antibodies ( mAb or moAb) are monospecific antibodies that are identical because they are produced by one type of immune cell [8] They noted that CR-50 reacted specifically with Cajal-Retzius neurons, whose functional role was unknown till then. The term Cajal–Retzius cell is applied to Reelin -producing neurons of the human embryonic marginal zone which display as a salient feature radial ascending

The downstream pathway of Reelin was clarified using other mutant mice, including yotari and scrambler. The yotari mouse is an autosomal recessive mutant It has a mutated Disabled homolog 1 ( Dab1) gene These mice have phenotypes similar to that of reeler but have no mutation in reelin. It was then demonstrated that the mouse disabled homologue 1 (Dab1) gene, which encodes a homolog of Drosophila disabled, is the gene responsible for the phenotypes of these mutant mice, and Dab1 protein was absent (yotari) or only barely (scrambler) detectable in these mutants. The Disabled-1 ( Dab1) gene encodes a key regulator of Reelin signaling [9] Targeted disruption of Dab1 also caused a phenotype similar to that of reeler.


wild-type mouse cortex
wild-type mouse cortex
Reeler cortex
Reeler cortex

The Reelin receptors, apolipoprotein E receptor 2 and very-low-density lipoprotein receptor, were discovered serendipitously by Trommsdorff et al, who found that the double knockout mice for apolipoprotein E receptor 2 and very-low-density lipoprotein receptor, which they generated for another experiment, showed defects in cortical layering similar to that in reeler. Key pathological findings in the Reeler brain structure Inversion of cortical layers A gene knockout is a genetic technique in which an organism is engineered to carry genes that have been made inoperative (have been "knocked out" of the organism [10]

In the July of 2006, a group of Japanese scientists published the first report of X-ray crystallography and electron tomography investigation of reelin structure. X-ray crystallography is a method of determining the arrangement of Atoms within a Crystal, in which a beam of X-rays strikes a crystal and scatters Electron Tomography (ET is a Tomography technique for obtaining detailed 3D structures of macromolecular objects [11]

Secretion and localization of reelin

Studies show that Reelin is absent from synaptic vesicles and is secreted via constitutive secretory pathway, being stored in Golgi secretory vesicles. In a Neuron, synaptic vesicles, also called neurotransmitter vesicles, store the various Neurotransmitters that are released during Calcium -regulated The secretory pathway is a series of steps a cell uses to move Proteins out of the cell a process known as secretion. The Golgi apparatus (also called the [12] Reelin's release rate is not regulated by depolarization, but strictly depends on its synthesis rate. In biology depolarization is a decrease in the Absolute value of a cell's Membrane potential. This relationship is similar to that reported for the secretion of other ECM proteins. In Biology, the extracellular matrix ( ECM) is the Extracellular part of animal tissue that usually provides structural support to the cells

In the cortex and hippocampus, reelin is secreted by Cajal-Retzius cells, Cajal cells, and Retzius cells during brain development. The term Cajal–Retzius cell is applied to Reelin -producing neurons of the human embryonic marginal zone which display as a salient feature radial ascending [13] In the cerebellum, Reelin is expressed first in the external granule cell layer (EGL) before the granule cell migration to the internal granule cell layer (IGL)[14]. Granular cell also refers to Juxtaglomerular cell in the kidney In Neuroscience, granule cells refer to tiny neurons (a type of In the adult brain, Reelin is expressed by GABA-ergic interneurons of the cortex and glutamatergic cerebellar neurons. Gamma-aminobutyric acid (GABA is the chief inhibitory Neurotransmitter in the Mammalian Central nervous system. An interneuron (also called association neuron, local circuit neuron or relay neuron) is a neuron which connects Afferent neurons and Efferent [15] Among GABAergic interneurons, Reelin seems to be detected predominantly in those expressing calretinin and calbindin, like bitufted, horizontal, and Martinotti cells, but not parvalbumin-expressing cells, like chandelier or basket neurons. Calretinin is a Vitamin D-dependent calcium-binding protein involved in Calcium signaling. Calbindin describes Calcium binding Proteins first described as the Vitamin D -dependent Calcium binding proteins in Intestine and Martinotti cells are small multipolar Neurons with short branching Dendrites They are scattered throughout various layers of the cerebral cortex sending their axons Parvalbumin is a Calcium binding albumin protein It has three EF hand motifs and is structurally related to Calmodulin and Troponin Chandelier neurons or chandelier cells are a subset of GABA -ergic cortical Interneurons They are described as Parvalbumin -containing and fast- Basket cells are inhibitory GABAergic Interneurons found in several brain regions the molecular layer of the Cerebellum, the Hippocampus [16][17] Outside the brain, reelin is found in adult mammalian blood, liver, pituitary pars intermedia, and adrenal chromaffin cells. The liver is a vital organ in the human body and is present in Vertebrates and some other animals Pars intermedia is the boundary between the anterior and posterior lobes of the Pituitary. Chromaffin cells are Neuroendocrine cells found in the medulla of the Adrenal gland (suprarenal gland - located above the kidneys and in other ganglia [18] In the liver, reelin is localized in hepatic stellate cells. Ito cells, also known as hepatic stellate cells, lipocytes, or fat-storing cells, are Pericytes found in the Perisinusoidal space [19] Its expression goes up when the liver is damaged, and returns to normal following its repair. [20]

Schema of the Reelin protein
Schema of the Reelin protein

Structure

Reelin is a secreted extracellular matrix glycoprotein composed of 3461 amino acids with a relative molecular mass of 388 kDa. In Biology, the extracellular matrix ( ECM) is the Extracellular part of animal tissue that usually provides structural support to the cells Not to be confused with Peptidoglycan. Glycoproteins are proteins that contain Oligosaccharide chains ( Glycans) covalently attached The unified atomic mass unit ( u) or Dalton ( Da) or sometimes universal mass unit, is an unit of Mass used to express

Reelin molecule starts with a signaling peptide 27 amino acids in length, followed by a region bearing similarity to F-spondin, marked as "SP" on the scheme, and by a region unique to reelin, marked as "H". Spondin 1 extracellular matrix protein, also known as SPON1, is a human Gene. Next come the 8 repeats of 300-350 amino acids. These are called reelin repeats and have an EGF motif at their center, dividing each repeat into two subrepeats, A and B. Epidermal growth factor or EGF is a Growth factor that plays an important role in the regulation of Cell growth, Proliferation, and Despite this interruption, the two subdomains make direct contact, resulting in a compact overall structure. [11]

The last comes a highly basic and short C-terminal region (CTR, marked "+") with a length of 32 amino acids. This region is extremely conservative, being 100% identical in all investigated mammals. It was thought that CTR is necessary for reelin secretion, because Orleans reeler mutation, which lacks a part of 8th repeat and the whole CTR, is unable to secrete the misshaped protein, leading to its concentration in cytoplasm. Key pathological findings in the Reeler brain structure Inversion of cortical layers However, one recent study has shown that the CTR is not essential for secretion, which is most probably hindered then reelin is cut along one of the repeats. [21]

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. [22] This splitting does not decrease the protein's activity, as constructs made of the predicted central fragments (repeats 3–6) bind to lipoprotein receptors, trigger Dab1 phosphorylation and mimic functions of reelin during cortical plate development. [23]

Function and mechanism of action

In the process of neural development, Reelin acts on migrating neuronal precursors and controls correct cell positioning in the cortex and other brain structures. The study of neural development draws on both Neuroscience and Developmental biology to describe the cellular and molecular mechanisms by which complex Nervous 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. [24] Dissociation detaches migrating neurons from the glial cells that are acting as their guides, converting them into individual cells that can strike out alone to find their final position. Glial cells, commonly called neuroglia or simply glia (Greek for "glue" are non- Neuronal cells that provide support and nutrition

In the adult brain, Reelin plays an important role by modulating cortical pyramidal neuron dendritic spine expression density, the branching of dendrites, and the expression of long-term potentiation. Dendrites (from Greek δένδρον déndron, “tree” are the branched projections of a Neuron that act to conduct the electrochemical In Neuroscience, long-term potentiation ( LTP) is the long-lasting improvement in communication between two Neurons that results from stimulating them

Mechanism of action

Reelin acts on two receptors:

which are members of the Low density lipoprotein receptor gene family. The very-low-density-lipoprotein receptor ( VLDLR) is a lipoprotein receptor that shows considerable similarity to the low-density-lipoprotein receptor. Low density lipoprotein receptor-related protein 8 apolipoprotein e receptor, also known as LRP8, is a human Gene.

The intracellular adaptor DAB1 binds to the VLDLR and ApoER2 through an NPxY motif and is involved in transmission of Reelin signals through these lipoprotein receptors. The Disabled-1 ( Dab1) gene encodes a key regulator of Reelin signaling

The proposal that the protocadherin CNR1 behaves as a Reelin receptor[25] has been disproved. Cadherins are a class of type-1 Transmembrane proteins They play important roles in Cell adhesion, ensuring that cells within tissues are bound together [23]

It has been shown that alpha-3-beta-1 integrin binds to the N-terminal region of reelin, a site distinct from the region of reelin shown to associate with other reelin receptors such as VLDLR/ApoER2. Integrins are Cell surface receptors that interact with the Extracellular matrix (ECM and mediate various intracellular signals. [26]

Reelin molecules have been shown[27] [28] to form a large protein complex, a disulfide-linked homodimer. In Chemistry, a disulfide bond is a single Covalent bond derived from the coupling of Thiol groups A dimer is a Chemical or Biological entity consisting of two subunits called Monomers which are held together by either Intramolecular forces If the homodimer fails to form, efficient tyrosine phosphorylation of DAB1 also fails. Phosphorylation is the addition of a Phosphate (PO4 group to a Protein molecule or a small molecule

Reelin-dependent strengthening of long-term potentiation is caused by ApoER2 interaction with NMDA receptor. Low density lipoprotein receptor-related protein 8 apolipoprotein e receptor, also known as LRP8, is a human Gene. The NMDA receptor ( NMDAR) is an Ionotropic receptor for Glutamate ( NMDA ( N -methyl D -aspartate is a name of its selective 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. [29]

Role in brain pathology

Lissencephaly

Disruptions of the RELN gene are condsidered to be the cause of the rare form of lissencephaly with cerebellar hypoplasia called Norman-Roberts syndrome. Lissencephaly, which literally means smooth brain, is a rare brain formation disorder characterized by the lack of normal convolutions (folds in the brain Lissencephaly 2, more commonly called Norman-Roberts syndrome, is a rare form of Lissencephaly caused by a mutation in the Reelin gene [30][31] The mutations disrupt splicing of RELN cDNA, resulting in low or undetectable amounts of reelin protein. In Molecular biology, splicing is a modification of an RNA after transcription, in which Introns are removed and Exons are joined In Genetics, complementary DNA ( cDNA) is DNA synthesized from a mature MRNA template in a reaction catalyzed by the enzyme Reverse The phenotype in these patients was characterized by hypotonia, ataxia, and developmental delay, with lack of unsupported sitting and profound mental retardation with little or no language development. A phenotype is any observable characteristic of an Organism, such as its morphology, Development, biochemical or physiological properties Hypotonia is a condition of abnormally low Muscle tone (the amount of tension or resistance to movement in a muscle often involving reduced muscle strength Ataxia (from Greek α- as a negative prefix + -τάξις, meaning "lack of order" is a neurological sign and symptom consisting Seizures and congenital lymphedema were also present. Lymphedema, also spelled lymphoedema, also known as lymphatic obstruction, is a condition of localized Fluid retention caused by a compromised

Schizophrenia

Reduced expression of reelin and its mRNA levels in the brains of schizophrenia sufferers had been reported in 1998[32] and 2000[33] and independently confirmed in the postmortem studies of hippocampus samples[34] and in the cortex studies. Schizophrenia ( from the Greek roots schizein (σχίζειν "to split" and phrēn Messenger ribonucleic acid ( mRNA) is a molecule of RNA encoding a chemical "blueprint" for a Protein product Schizophrenia ( from the Greek roots schizein (σχίζειν "to split" and phrēn [35][36] The reduction may reach up to 50% in some brain regions and is coupled with reduced expression of GAD-67 enzyme,[37] which catalyses the transition of glutamate to GABA. Glutamate decarboxylase (GAD is an Enzyme that catalyzes the decarboxylation of Glutamate to GABA and CO2 Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins Glutamic acid (abbreviated as Glu or E) is one of the 20 Alpha Amino acids It is not among the human Essential amino acids Its Gamma-aminobutyric acid (GABA is the chief inhibitory Neurotransmitter in the Mammalian Central nervous system. Blood levels of reelin and its isoforms are also altered in schizophrenia, along with other mood disorders, according to one study. A blood test is a laboratory analysis performed on a Blood sample that is usually extracted from a Vein in the arm using a needle, or via A protein isoform is a version of a Protein with only small differences to another isoform of the same protein [38] 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. [39]

Epigenetic hypermethylation of DNA in schizophrenia patients is proposed as a cause of the reduction,[40][41] in accordance with the knowledge that administration of methionine to schizophrenic patients results in a profound exacerbation of schizophrenia symptoms in sixty to seventy percent of patients, a fact discovered in the 1960's. In Biology, the term epigenetics refers to changes in Gene expression caused by mechanisms other than changes in the underlying DNA sequence Methionine ( abbreviated as Met or M) is an α- Amino acid with the Chemical formula HO2CCH(NH2CH2CH2SCH3 [42][43][44][45] In contrast with initial data, subsequent studies failed to confirm the hypermethylation. [46][47] A postmortem study comparing DNMT1 and Reelin mRNA expression in cortical layers I and V of schizophrenic patients and normal controls demonstrated that in the layer V both DNMT1 and Reelin levels were normal, while in the layer I DNMT1 was threefold higher, probably leading to the twofold decrease in the Reelin expression. In Biochemistry, the DNA methyltransferase (DNA MTase family of Enzymes catalyze the transfer of a Methyl group to DNA. [48] Methylation inhibitors and histone deacetylase inhibitors, such as valproic acid, increase reelin mRNA levels,[49] [50] [51] while L-methionine treatment downregulates the phenotypic expression of reelin. Methylation is a term used in the chemical sciences to denote the attachment or substitution of a methyl group on various substrates. Histone deacetylases (HDAC ( EC number 351 are a class of Enzymes that remove Acetyl groups from an ε-N-acetyl Lysine Amino acid Valproic acid ( VPA) is a Chemical compound that has found clinical use as an Anticonvulsant and mood-stabilizing drug, primarily in [52]

Heterozygous reeler mouse, which is haploinsufficient for the reeler gene, shares several neurochemical and behavioral abnormalities with schizophrenia and bipolar disorder[53], but considered as not suitable for use as a genetic mouse model of schizophrenia. Zygosity refers to the genetic condition of a Zygote. In genetics zygosity describes the similarity or dissimilarity of DNA between Homologous Haploinsufficiency occurs when a Diploid organism only has a single functional copy of a gene (with the other copy inactivated by Mutation) and the single [54]

Bipolar disorder

Decrease in RELN expression is typical of bipolar disorder with psychosis, but is not characteristic of patients with major depression without psychosis. [33]

Autism

A number of studies have shown an association between the reelin gene and autism[55] [56]. Language development. The terminology Language development. The terminology A couple of studies were unable to duplicate linkage findings, however. [57][58]

Temporal Lobe Epilepsy

Decreased reelin expression in the hippocampal tissue samples from patients with temporal lobe epilepsy was found to be directly correlated to the extent of granule cell dispersion, a major feature of the disease. Temporal lobe epilepsy is a form of focal Epilepsy, a chronic neurological condition characterized by recurrent Seizures While Granular cell also refers to Juxtaglomerular cell in the kidney In Neuroscience, granule cells refer to tiny neurons (a type of [59] [60] 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. [61]

Alzheimer's disease

According to one study, reelin expression and glycosylation patterns are altered in Alzheimer's disease. Alzheimer's disease ( AD) also called Alzheimer disease or simply Alzheimer's, is the most common form of Dementia. Glycosylation is the enzymatic process that links Saccharides to produce glycans, either free or attached to Proteins and Lipids This enzymatic Alzheimer's disease ( AD) also called Alzheimer disease or simply Alzheimer's, is the most common form of Dementia. 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. [62] This finding correlates with an earlier study showing the presence of Reelin associated with amyloid plaques in a transgenic AD mouse model. [63]

Recommended reading

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

External links

Articles, publications, webpages

Figures and images

References

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