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--><ref name="pmid18593473">{{cite journal |author=Keilani S, Sugaya K |title=Reelin induces a radial glial phenotype in human neural progenitor cells by activation of Notch-1 |journal=[[BMC Dev. Biol.]] |volume=8 |issue=1 |pages=69 |year=2008 |month=July |pmid=18593473 |doi=10.1186/1471-213X-8-69 |url=}}</ref>
--><ref name="pmid18593473">{{cite journal |author=Keilani S, Sugaya K |title=Reelin induces a radial glial phenotype in human neural progenitor cells by activation of Notch-1 |journal=[[BMC Dev. Biol.]] |volume=8 |issue=1 |pages=69 |year=2008 |month=July |pmid=18593473 |doi=10.1186/1471-213X-8-69 |url=}}</ref>

One study shows that proper corticogenesis ''in vivo'' is highly dependent upon reelin being processed by embrionic neurons,<ref name="pmid17442808"/> which are supposed to secrete some unindentified metalloproteinases that free the central signal-competent part of the protein. Some other unknown proteolytic mechanisms may also play a role.<!--

--><ref name="pmid12959647">{{cite journal |author=Lugli G, Krueger JM, Davis JM, Persico AM, Keller F, Smalheiser NR |title=Methodological factors influencing measurement and processing of plasma reelin in humans |journal=[[BMC Biochem.]] |volume=4 |issue= |pages=9 |year=2003 |month=September |pmid=12959647 |pmc=200967 |doi=10.1186/1471-2091-4-9 |url=http://www.biomedcentral.com/1471-2091/4/9}}</ref><!--

--> It is supposed that full-sized reelin stucks to the extracellular matrix fibers on the higher levels, and the central fragments, as they are being freed up by the breaking up of reelin, are able to permeate into the lower levels.<!--

--><ref name="pmid17442808">{{cite journal |author=Jossin Y, Gui L, Goffinet AM |title=Processing of Reelin by embryonic neurons is important for function in tissue but not in dissociated cultured neurons |journal=[[J. Neurosci.]] |volume=27 |issue=16 |pages=4243–52 |year=2007 |month=April |pmid=17442808 |doi=10.1523/JNEUROSCI.0023-07.2007 |url=http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=17442808}}</ref><!--

--> It is possible that as neuroblasts reach the higher levels they stop their migration either because of the heightened combined expression of all forms of reelin, or due to the peculiar mode of action of the full-sized reelin molecules and its homodimers.<!--

--><ref name="reelin_book_2008"/>


== Role in brain pathology ==
== Role in brain pathology ==

Revision as of 19:43, 22 August 2008

Template:PBB Reelin is a protein found mainly in the brain, but also in the spinal cord, blood and other body organs and tissues. Reelin is crucial for regulating the processes of neuronal migration and positioning in the developing brain. Besides this important role in the early period, reelin continues to work in the adult brain. It modulates the synaptic plasticity by enhancing LTP induction and maintenance.[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.

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

Reelin's name comes from the abnormal reeling gait of reeler mice,[4] which were found to have a deficiency of this brain protein and were homozygous for mutation of the RELN gene, which encodes reelin synthesis.

The primary phenotype associated with loss of reelin function is a rough inversion of cortical layers. The mice heterozygous for the reelin gene, while having little neuroanatomical defects, display the endophenotypic traits linked to psychotic disorders.[5]

Video: the reeler mice mutants, first described in 1951 by D.S.Falconer, were later found to lack reelin protein.

Discovery

Normal and Reeler mice brain slices.

Mutant mice provide insight into the underlying molecular mechanisms of the development of the CNS. Useful spontaneous mutations were first identified by scientists interested in motor behavior, and it proved relatively easy to screen littermates for mice that showed difficulties moving around the cage. A number of such mice were found and given descriptive names such as reeler, weaver, lurcher, nervous, and staggerer.

The "reeler" mouse was first described in the 1951 by D.S.Falconer.[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.[6] 1970's brought the discovery of cellular layers inversion in the mice neocortex[7], 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[8]. Almost immediately, Japanese scientists at Kochi Medical School had successfully created the first monoclonal antibody for reelin, called CR-50.[9] They noted that CR-50 reacted specifically with Cajal-Retzius neurons, whose functional role was unknown till then.

The Reelin receptors, apolipoprotein E receptor 2 (ApoER2) and very-low-density lipoprotein receptor (VLDLR), were discovered serendipitously by Trommsdorff et al, who found that the double knockout mice for ApoER2 and VLDLR, which they generated for another experiment, showed defects in cortical layering similar to that in reeler.[10]

The downstream pathway of Reelin was further clarified using other mutant mice, including yotari and scrambler. These mutants 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 is responsible for the phenotypes of these mutant mice, as Dab1 protein was absent (yotari) or only barely (scrambler) detectable in these mutants.[11] Targeted disruption of Dab1 also caused a phenotype similar to that of reeler. Pinpointing the DAB1 as a pivotal regulator of the reelin signaling cascade started the tedious process of deciphering its complex interactions.

There followed a series of important findings 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.[12] These aspects have been summarized by the leading researchers in a book called "Reelin Glycoprotein: Structure, Biology and Roles in Health and Disease" that saw print in 2008.[13]

Tissue distribution and secretion

File:Reeler ontogenesis.png
Corticogenesis in a normal (left) and reeler (right) mice

Studies show that Reelin is absent from synaptic vesicles and is secreted via constitutive secretory pathway, being stored in Golgi secretory vesicles.[14] Reelin's release rate is not regulated by depolarization, but strictly depends on its synthesis rate. This relationship is similar to that reported for the secretion of other ECM proteins.

During the brain development, reelin is secreted in the cortex and hippocampus by Cajal-Retzius cells, Cajal cells, and Retzius cells.[15] Reelin-expressing cells in the prenatal and early postnatal brain are predominantly found in the marginal zone (MZ) of the cortex and in the temporary subpial granular layer (SGL), which is manifested to the highest extent in human,[16] and in the hippocampal stratum lacunosum-moleculare and the upper marginal layer of the dentate gyrus.

In the developing cerebellum, Reelin is expressed first in the external granule cell layer (EGL) before the granule cell migration to the internal granule cell layer (IGL)[17].

Peaking just after the birth, the synthesis of reelin then becomes more diffuse compared in the contrast with the distincly laminar expression of the developing brain. In the adult brain, Reelin is expressed by GABA-ergic interneurons of the cortex and glutamatergic cerebellar neurons.[18] 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.[19][20] Outside the brain, reelin is found in adult mammalian blood, liver, pituitary pars intermedia, and adrenal chromaffin cells. [21] In the liver, reelin is localized in hepatic stellate cells.[22] Its expression goes up when the liver is damaged, and returns to normal following its repair. [23]

Schema of the Reelin protein

In the eyes reelin is secreted by retinal ganglion cells and is also found in the endothelial layer of the cornea.[24] Similar to liver, the expression goes up after an injury.

Structure

The structure of two reelin repeats as revealed by X-ray crystallography and electron tomography. Nogi et al., 2006,[25] PDB: 2E26​.

Reelin is a secreted extracellular matrix glycoprotein composed of 3461 amino acids with a relative molecular mass of 388 kDa; its structural features allow for an enzymatic activity, making it a serine protease.[26] Murine RELN gene consists of 65 exons spanning approximately 450 kb.[27] One exon, coding for only two amino acids near the protein's C-terminal, undergoes alternative splicing, but the exact functional impact of this is unknown.[13] Two transcription initiation sites and two polyadenilation sites are identified in the gene structure.[27]

Reelin molecule starts with a signaling peptide 27 amino acids in length, followed by a region bearing similarity to F-spondin, marked as "SP" on the scheme, and by a region unique to reelin, marked as "H". Next come the 8 repeats of 300-350 amino acids. These are called reelin repeats and have an EGF motif at their center, dividing each repeat into two subrepeats, A and B. Despite this interruption, the two subdomains make direct contact, resulting in a compact overall structure.[25]

The last comes a highly basic and short C-terminal region (CTR, marked "+") with a length of 32 amino acids. This region is extremely conservative, being 100% identical in all investigated mammals. It was thought that CTR is necessary for reelin secretion, because Orleans reeler mutation, which lacks a part of 8th repeat and the whole CTR, is unable to secrete the misshaped protein, leading to its concentration in cytoplasm. However, one recent study has shown that the CTR is not essential for secretion, which is most probably hindered then reelin is cut along one of the repeats.[28]

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.[29] 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.[30] Moreover, the processing of reelin by embryonic neurons may be neccessary for proper corticogenesis.[31]

Function

The pivotal functions of Reelin are the regulation of corticogenesis and neuronal cell positioning in the prenatal period, but the protein is also implicated in a number of other processes, and the research is ongoing.

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.

A number of non-nervous tissues and organs express reelin in the developing organism, with the expression sharply going down after the organ had been formed. The role of the protein here is largely unexplored, because the knockout mice show no major pathology in these organs. In the adult organism the non-neural expression is much less widespread, but goes up sharply when some organs are injured.[24][23] The exact function of reelin upregulation following an injury is still being researched.

Reelin controls the direction of radial glia growth. A fragment of an illustration from Nomura T. et al., 2008.[32] 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.

On the other hand, reelin's role in the growing CNS is more important and more explored. It promotes the differentiation of progenitor cells into radial glia and affects the orientation of its fibers, which serve as the guides for the migrating neuroblasts.[33] The position of reelin-secreting cell layer is important, because the fibers orient themselves in the direction of its higher concentration.[32]

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

Increased reelin expression changes the morphology of migrating neurons: unlike the round neurons with short branches (C) they assume bipolar shape (D) and attach themselves (E) to the radial glia fibers that are extending in the direction of reelin-expressing cells. Nomura T. et al., 2008.[32]

There is no agreement concerning the role of reelin in the proper positioning of cortical layers. The initial suggestion that the protein is a stop signal for the migrating cells is supported by its ability to induce the dissociation,[34] 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,[35] 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.

The protein supposedly acts 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.[34] Dissociation detaches migrating neurons from the glial cells that are acting as their guides, converting them into individual cells that can strike out alone to find their final position.

In the adult 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 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. 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.[36]

Reelin also plays an important role in the adult brain by modulating cortical pyramidal neuron dendritic spine expression density, the branching of dendrites, and the expression of long-term potentiation[2] as its secretion is continued diffusely by the GABAegric cortical interneurons those origin is traced to the medial ganglionic eminence.

One study suggests that reelin may be the part of the mechanism behind the developmental change in the subunit composition of NMDA receptor, a major player in the memory and neuroplasticity processes. Reelin was shown to increase the mobility of its NR2B subunit.[37]

Evolutionary significance

Cajal-Retzius cells, as drawn by Cajal in 1891. The development of a distinct layer of these reelin-secreting cells played a major role in brain evolution.
Neuronal development: mammals (left) and avians (right) have different patterns of reelin expression (pink). Nomura T. et al., 2008.[32]

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 amniote predeccessor into multiple-layered cortex of contemporary mammals.[38] 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.[39] Reelin is present in the telencephalon of all the vertebrates studied so far, but the pattern of expression is widely differential. For example, in zebra fish there are no Cajal-Retzius cells and the protein is being secreted by other neurons.[40][41] These cells do not form a dedicated layer in amphibians, and radial migration in their brains is very weak.[40]

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.[32] There are conflicting data concerning the importance of this layer,[35] and these are explained in the literature either by the existence of an additional signaling positional mechanism that interacts with the reelin cascade,[35] or by the assumption that mice that are used in such experiments have reduntant secretion of reelin[42] compared with more localized synthesis in the human brain.[16]

Cajal-Retzius cells, most of which disappear around the time of birth, coexpress reelin with the HAR1 gene that is thought to have undergone the most significant evolutionary change in humans compared with chimpanzee, being the most «evolutionary accelerated» of the genes from the human accelerated regions discovered in 2006.[43] There is evidence of an ongoing evolution in the reelin pathway: DAB1 gene variant was described in 2007 that has spread recently in the Chinese but not in another populations.[44][45]

Mechanism of action

The main reelin signaling cascade (ApoER2 and VLDLR) and its interaction with LIS1. Zhang et al., 2008[46]

The main action of reelin is apparently conducted through the two members of Low density lipoprotein receptor gene family, VLDLR and the ApoER2. It also has been shown that alpha-3-beta-1 integrin receptor binds the N-terminal region of reelin, a site distinct from the region of reelin shown to associate with VLDLR/ApoER2.[47] The proposal that the protocadherin CNR1 behaves as a Reelin receptor[48] has been disproven.[30]

Reelin receptors are present on both neurons and glial cells, with one study showing the radial glia to express the same amount of ApoER2 but being ten times less rich in VLDLR.[33] One study suggests that beta-1 integrin receptors on glial cells play more important role in neuronal layering than the same receptors on the migrating neuroblasts.[49]

The intracellular adaptor DAB1 binds to the VLDLR and ApoER2 through an NPxY motif and is involved in transmission of Reelin signals through these lipoprotein receptors. It becomes phosphorylated and apparently stimulates the actin cytoskeleton to change its shape, affecting the proportion of integrin receptors on the cell surface, which leads to the change in adhesion. Phosphorylation of DAB1 leads to its ubiquitination and subsequent degradation, and this explains the hightened levels of DAB1 in the absense of reelin.[50] Such negative feedback is thought to be important for proper cortical lamination.[51]

Reelin stimulates the progenitor cells to differentiate into radial glia, inducing the expression of radial glial marker BLBP by affecting the NOTCH1 cascade. A fragment of an illustration from Keilani et al., 2008.[52]

A protein having an important role in lissencephaly and accordingly called LIS1 (PAFAH1b1), was shown to interact with the intracellular segment of VLDLR, thus reacting to the activation of reelin pathway.[46]

The two main reelin receptors seem to have slightly different roles: according to one study, VLDLR conducts the stop signal, while ApoER2 is essential for the migration of late-born neocortical neurons.[53]

Reelin molecules have been shown[54] [55] to form a large protein complex, a disulfide-linked homodimer. If the homodimer fails to form, efficient tyrosine phosphorylation of DAB1 in vitro fails. But reelin itself can cut the peptide bonds holding other proteins together, being a serine protease,[26] and this may affect the cellular adhesion and migration processes.

Reelin-dependent strengthening of long-term potentiation is caused by ApoER2 interaction with NMDA receptor. This interaction happens when ApoER2 has a region coded by exon 19. ApoER2 gene is alternatively spliced, with the exon 19-containing variant more actively produced during periods of activity.[56]

The activation of dendrite growth by reelin is apparently conducted throuth Src family kinases and is dependent upon the expression of Crk family proteins.[57]

One study shows that reelin somehow activates the signaling cascade of Notch-1, inducing the expression of FABP7 and prompting progenitor cells to assume radial glial phenotype.[52]

One study shows that proper corticogenesis in vivo is highly dependent upon reelin being processed by embrionic neurons,[31] which are supposed to secrete some unindentified metalloproteinases that free the central signal-competent part of the protein. Some other unknown proteolytic mechanisms may also play a role.[58] It is supposed that full-sized reelin stucks 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.[31] It is possible that as neuroblasts 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.[59]

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.[60][61] The mutations disrupt splicing of RELN cDNA, resulting in low or undetectable amounts of reelin protein. The phenotype in these patients was characterized by hypotonia, ataxia, and developmental delay, with lack of unsupported sitting and profound mental retardation with little or no language development. Seizures and congenital lymphedema were also present.

Schizophrenia

Reduced expression of reelin and its mRNA levels in the brains of schizophrenia sufferers had been reported in 1998[62] and 2000[63] and independently confirmed in the postmortem studies of hippocampus samples[64] and in the cortex studies.[65][66] The reduction may reach up to 50% in some brain regions and is coupled with reduced expression of GAD-67 enzyme,[67] which catalyses the transition of glutamate to GABA. Blood levels of reelin and its isoforms are also altered in schizophrenia, along with other mood disorders, according to one study.[68] 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.[69]

Epigenetic hypermethylation of DNA in schizophrenia patients is proposed as a cause of the reduction,[70][71] 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.[72][73][74][75] In contrast with initial data, subsequent studies failed to confirm the hypermethylation.[76][77] 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. [78] Methylation inhibitors and histone deacetylase inhibitors, such as valproic acid, increase reelin mRNA levels,[79] [80] [81] while L-methionine treatment downregulates the phenotypic expression of reelin. [82]

Heterozygous reeler mouse, which is haploinsufficient for the reeler gene, shares several neurochemical and behavioral abnormalities with schizophrenia and bipolar disorder[83], but considered as not suitable for use as a genetic mouse model of schizophrenia.[84]

Bipolar disorder

Decrease in RELN expression is typical of bipolar disorder with psychosis, but is not characteristic of patients with major depression without psychosis.[63]

Autism

A number of studies have shown an association between the reelin gene and autism[85] [86]. A couple of studies were unable to duplicate linkage findings, however.[87][88]

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 that is noted in 45%-73% of patients.[89] [90] 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.[91]

Alzheimer's disease

According to one study, reelin expression and glycosylation patterns are altered in Alzheimer's disease. In the cortex of the patients, reelin levels were 40% higher compared with controls, but the cerebellar levels of the protein remain normal in the same patients.[92] This finding correlates with an earlier study showing the presence of Reelin associated with amyloid plaques in a transgenic AD mouse model. [93]

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  93. ^ Wirths O, Multhaup G, Czech C; et al. (2001). "Reelin in plaques of beta-amyloid precursor protein and presenilin-1 double-transgenic mice". Neurosci. Lett. 316 (3): 145–8. PMID 11744223. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

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  1. ^ Cite error: The named reference dong was invoked but never defined (see the help page).
  2. ^ a b Cite error: The named reference liss2000 was invoked but never defined (see the help page).
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