Reelin

Reelin is implicated in pathogenesis of several brain diseases. Significantly lowered expression of the protein have been found in schizophrenia and psychotic bipolar disorder, but the cause of it is uncertain as studies show that psychotropic medication itself affects RELN expression and the epigenetic hypothesis aimed at explaining the changed levels has received some contradictory evidence. 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, Falconer DS (1951) "2 new mutants, trembler and reeler, with neurological actions in the house mouse (mus-musculus l)" Journal of Genetics 50 (2): 192-201 [http://cercor.oxfordjournals.org/cgi/external_ref?access_num=A1951XX17400002&link_type=ISI] ] 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. cite journal |author=Tueting P, Doueiri MS, Guidotti A, Davis JM, Costa E |title=Reelin down-regulation in mice and psychosis endophenotypes |journal=Neurosci Biobehav Rev |volume=30 |issue=8 |pages=1065–77 |year=2006 |pmid=16769115 |doi=10.1016/j.neubiorev.2006.04.001 ] [
D.S.Falconer, were later found to lack reelin protein.]

Discovery

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.

In 1995, the RELN gene was mapped to chromosome 7q22 and sequenced by Gabriella D'Arcangelo and colleagues. cite journal |author=D'Arcangelo G, Miao GG, Chen SC, Soares HD, Morgan JI, Curran T |title=A protein related to extracellular matrix proteins deleted in the mouse mutant reeler |journal=Nature |volume=374 |issue=6524 |pages=719–23 |year=1995 |month=April |pmid=7715726 |doi=10.1038/374719a0 |url=] Almost immediately, Japanese scientists at Kochi Medical School had successfully created the first monoclonal antibody for reelin, called CR-50. cite journal |author=Ogawa M, Miyata T, Nakajima K, "et al" |title=The reeler gene-associated antigen on Cajal-Retzius neurons is a crucial molecule for laminar organization of cortical neurons |journal=Neuron |volume=14 |issue=5 |pages=899–912 |year=1995 |month=May |pmid=7748558 |doi= 10.1016/0896-6273(95)90329-1] They noted that CR-50 reacted specifically with Cajal-Retzius neurons, whose functional role was unknown until 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. cite journal |author=Trommsdorff M, Gotthardt M, Hiesberger T, "et al" |title=Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2 |journal=Cell |volume=97 |issue=6 |pages=689–701 |year=1999 |month=June |pmid=10380922 |url= |doi=10.1016/S0092-8674(00)80782-5]

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. cite journal |author=Sheldon M, Rice DS, D'Arcangelo G, "et al" |title=Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice |journal=Nature |volume=389 |issue=6652 |pages=730–3 |year=1997 |month=October |pmid=9338784 |doi=10.1038/39601 |url=] 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. ] - a search in the Google Scholar] 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. cite book
last =
first =
editor = Hossein S. Fatemi
authorlink =
title = Reelin Glycoprotein: Structure, Biology and Roles in Health and Disease
publisher = Springer
series =
year = 2008
doi =
url = http://www.springer.com/biomed/neuroscience/book/978-0-387-76760-4
pages = 444
isbn = 978-0-387-76760-4 ]

Tissue distribution and secretion

Studies show that Reelin is absent from synaptic vesicles and is secreted via constitutive secretory pathway, being stored in Golgi secretory vesicles. cite journal |author=Lacor PN, Grayson DR, Auta J, Sugaya I, Costa E, Guidotti A |title=Reelin secretion from glutamatergic neurons in culture is independent from neurotransmitter regulation |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue=7 |pages=3556–61 |year=2000 |month=March |pmid=10725375 |pmc=16278 |doi=10.1073/pnas.050589597 ] 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. cite journal |author=Meyer G, Goffinet AM, Fairén A |title=What is a Cajal-Retzius cell? A reassessment of a classical cell type based on recent observations in the developing neocortex |journal=Cereb. Cortex |volume=9 |issue=8 |pages=765–75 |year=1999 |month=December |pmid=10600995 |url= |doi=10.1093/cercor/9.8.765] 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, cite journal |author=Meyer G, Goffinet AM |title=Prenatal development of reelin-immunoreactive neurons in the human neocortex |journal=J. Comp. Neurol. |volume=397 |issue=1 |pages=29–40 |year=1998 |month=July |pmid=9671277 |doi=10.1002/(SICI)1096-9861(19980720)397:1 |doi_brokendate=2008-08-23] and in the hippocampal stratum lacunosum-moleculare and the upper marginal layer of the dentate gyrus.

tructure

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. Murine RELN gene consists of 65 exons spanning approximately 450 kb. cite journal |author=Royaux I, Lambert de Rouvroit C, D'Arcangelo G, Demirov D, Goffinet AM |title=Genomic organization of the mouse reelin gene |journal=Genomics |volume=46 |issue=2 |pages=240–50 |year=1997 |month=December |pmid=9417911|url= |doi=10.1006/geno.1997.4983] 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. Two transcription initiation sites and two polyadenilation sites are identified in the gene structure.

The Reelin protein 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 comes 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. cite journal |author=Nogi T, Yasui N, Hattori M, Iwasaki K, Takagi J |title=Structure of a signaling-competent reelin fragment revealed by X-ray crystallography and electron tomography |journal=EMBO J. |volume=25 |issue=15 |pages=3675–83 |year=2006 |month=August |pmid=16858396 |pmc=1538547 |doi=10.1038/sj.emboj.7601240 |url=]

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 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. cite journal |author=Nakano Y, Kohno T, Hibi T, "et al" |title=The extremely conserved C-terminal region of Reelin is not necessary for secretion but is required for efficient activation of downstream signaling |journal=J. Biol. Chem. |volume=282 |issue=28 |pages=20544–52 |year=2007 |month=July |pmid=17504759 |doi=10.1074/jbc.M702300200 ]

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. cite journal |author=Lambert de Rouvroit C, de Bergeyck V, Cortvrindt C, Bar I, Eeckhout Y, Goffinet AM |title=Reelin, the extracellular matrix protein deficient in reeler mutant mice, is processed by a metalloproteinase |journal=Exp. Neurol. |volume=156 |issue=1 |pages=214–7 |year=1999 |month=March |pmid=10192793 |doi=10.1006/exnr.1998.7007 |url=] 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. cite journal |author=Jossin Y, Ignatova N, Hiesberger T, Herz J, Lambert de Rouvroit C, Goffinet AM |title=The central fragment of Reelin, generated by proteolytic processing in vivo, is critical to its function during cortical plate development |journal=J. Neurosci. |volume=24 |issue=2 |pages=514–21 |year=2004 |month=January |pmid=14724251 |doi=10.1523/JNEUROSCI.3408-03.2004 |url=] Moreover, the processing of reelin by embryonic neurons may be necessary for proper corticogenesis. 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=]

Function

The primary 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. The exact function of reelin upregulation following an injury is still being researched.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. cite journal |author=Hartfuss E, Förster E, Bock HH, "et al" |title=Reelin signaling directly affects radial glia morphology and biochemical maturation |journal=Development |volume=130 |issue=19 |pages=4597–609 |year=2003 |month=October |pmid=12925587 |doi=10.1242/dev.00654 |url=] The position of reelin-secreting cell layer is important, because the fibers orient themselves in the direction of its higher concentration. cite journal |author=Nomura T, Takahashi M, Hara Y, Osumi N |title=Patterns of neurogenesis and amplitude of Reelin expression are essential for making a mammalian-type cortex |journal=PLoS ONE |volume=3 |issue=1 |pages=e1454 |year=2008 |pmid=18197264 |pmc=2175532 |doi=10.1371/journal.pone.0001454 |url=]

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

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, 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, cite journal |author=Yoshida M, Assimacopoulos S, Jones KR, Grove EA |title=Massive loss of Cajal-Retzius cells does not disrupt neocortical layer order |journal=Development |volume=133 |issue=3 |pages=537–45 |year=2006 |month=February |pmid=16410414 |doi=10.1242/dev.02209 |url=] 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 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. cite journal |author=Hack I, Bancila M, Loulier K, Carroll P, Cremer H |title=Reelin is a detachment signal in tangential chain-migration during postnatal neurogenesis |journal=Nat. Neurosci. |volume=5 |issue=10 |pages=939–45 |year=2002 |month=October |pmid=12244323 |doi=10.1038/nn923 |url=] 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. cite journal | author = Frotscher M, Haas CA, Förster E | title = Reelin controls granule cell migration in the dentate gyrus by acting on the radial glial scaffold | journal = Cereb. Cortex | volume = 13 | issue = 6 | pages = 634–40 | year = 2003 | month = June | pmid = 12764039 | url = | doi = 10.1093/cercor/13.6.634 ]

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 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. cite journal |author=Groc L, Choquet D, Stephenson FA, Verrier D, Manzoni OJ, Chavis P |title=NMDA receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein Reelin |journal=J. Neurosci. |volume=27 |issue=38 |pages=10165–75 |year=2007 |pmid=17881522 |doi=10.1523/JNEUROSCI.1772-07.2007]

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.] 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. cite journal |author=Bar I, Lambert de Rouvroit C, Goffinet AM |title=The evolution of cortical development. An hypothesis based on the role of the Reelin signaling pathway |journal=Trends Neurosci. |volume=23 |issue=12 |pages=633–8 |year=2000 |month=December |pmid=11137154|url= |doi=10.1016/S0166-2236(00)01675-1] 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. cite journal |author=Molnár Z, Métin C, Stoykova A, "et al" |title=Comparative aspects of cerebral cortical development |journal=Eur. J. Neurosci. |volume=23 |issue=4 |pages=921–34 |year=2006 |month=February |pmid=16519657 |pmc=1931431 |doi=10.1111/j.1460-9568.2006.04611.x |url=] 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. cite journal |author=Costagli A, Kapsimali M, Wilson SW, Mione M |title=Conserved and divergent patterns of Reelin expression in the zebrafish central nervous system |journal=J. Comp. Neurol. |volume=450 |issue=1 |pages=73–93 |year=2002 |month=August |pmid=12124768 |doi=10.1002/cne.10292 |url=] These cells do not form a dedicated layer in amphibians, and radial migration in their brains is very weak. cite journal |author=Pérez-García CG, González-Delgado FJ, Suárez-Solá ML, "et al" |title=Reelin-immunoreactive neurons in the adult vertebrate pallium |journal=J. Chem. Neuroanat. |volume=21 |issue=1 |pages=41–51 |year=2001 |month=January |pmid=11173219 |url= |doi=10.1016/S0891-0618(00)00104-6]

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. There are conflicting data concerning the importance of this layer, and these are explained in the literature either by the existence of an additional signaling positional mechanism that interacts with the reelin cascade, or by the assumption that mice that are used in such experiments have redundant secretion of reelin cite journal |author=Goffinet AM |title=What makes us human? A biased view from the perspective of comparative embryology and mouse genetics |journal=J Biomed Discov Collab |volume=1 |issue= |pages=16 |year=2006 |pmid=17132178 |pmc=1769396 |doi=10.1186/1747-5333-1-13 |url=] compared with more localized synthesis in the human brain. cite journal |author=Meyer G, Goffinet AM |title=Prenatal development of reelin-immunoreactive neurons in the human neocortex |journal=J. Comp. Neurol. |volume=397 |issue=1 |pages=29–40 |year=1998 |month=July |pmid=9671277 |doi=10.1002/(SICI)1096-9861(19980720)397:1 |url= |doi_brokendate=2008-08-23]

Mechanism of action

Reelin receptors are present on both neurons and glial cells, with one study showing that the radial glia express the same amount of ApoER2 but being ten times less rich in VLDLR. 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.cite journal |author=Belvindrah R, Graus-Porta D, Goebbels S, Nave KA, Müller U |title=Beta1 integrins in radial glia but not in migrating neurons are essential for the formation of cell layers in the cerebral cortex |journal=J. Neurosci. |volume=27 |issue=50 |pages=13854–65 |year=2007 |month=December |pmid=18077697 |doi=10.1523/JNEUROSCI.4494-07.2007 ]

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 absence of reelin. cite journal |author=Feng L, Allen NS, Simo S, Cooper JA |title=Cullin 5 regulates Dab1 protein levels and neuron positioning during cortical development |journal=Genes Dev. |volume=21 |issue=21 |pages=2717–30 |year=2007 |month=November |pmid=17974915 |pmc=2045127 |doi=10.1101/gad.1604207 |url=] Such negative feedback is thought to be important for proper cortical lamination. cite journal | author = Kerjan G, Gleeson JG | title = A missed exit: Reelin sets in motion Dab1 polyubiquitination to put the break on neuronal migration | journal = Genes Dev. | volume = 21 | issue = 22 | pages = 2850–4 | year = 2007 | month = November | pmid = 18006681 | doi = 10.1101/gad.1622907 | url = ] 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. cite journal | author = Zhang G, Assadi AH, McNeil RS, Beffert U, Wynshaw-Boris A, Herz J, Clark GD, D’Arcangelo G. | title = The Pafah1b complex interacts with the Reelin receptor VLDLR | journal = PLoS ONE | volume = 2 | issue = 2 | pages = e252 | year = 2007 | pmid = 17330141 | pmc = 1800349 | doi = 10.1371/journal.pone.0000252 | url = ]

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. cite journal |author=Hack I, Hellwig S, Junghans D, Brunne B, Bock HH, Zhao S, Frotscher M |title=Divergent roles of ApoER2 and Vldlr in the migration of cortical neurons |journal=Development |volume=134 |issue=21 |pages=3883–91 |year=2007 |pmid=17913789 |doi=10.1242/dev.005447]

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. cite journal |author=Beffert U, Weeber EJ, Durudas A, "et al" |title=Modulation of synaptic plasticity and memory by Reelin involves differential splicing of the lipoprotein receptor Apoer2 |journal=Neuron |volume=47 |issue=4 |pages=567–79 |year=2005 |month=August |pmid=16102539 |doi=10.1016/j.neuron.2005.07.007 |url=http://jax.herzlab.org/Course2006/presentations/Beffert2005.pdf] According to one study, the hippocampal reelin expression rapidly goes up when there is need to store a memory, as demethylases open up the RELN gene. cite journal |author=Miller CA, Sweatt JD |title=Covalent modification of DNA regulates memory formation |journal=Neuron |volume=53 |issue=6 |pages=857–69 |year=2007 |month=March |pmid=17359920 |doi=10.1016/j.neuron.2007.02.022 |url=]

One study shows that proper corticogenesis "in vivo" is highly dependent upon reelin being processed by embrionic neurons, which are thought to secrete some as yet unidentified metalloproteinases that free the central signal-competent part of the protein. Some other unknown proteolytic mechanisms may also play a role. 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=] 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. 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.

Role in brain pathology

Lissencephaly

Disruptions of the RELN gene are considered to be the cause of the rare form of lissencephaly with cerebellar hypoplasia called Norman-Roberts syndrome. cite journal |author=Hong SE, Shugart YY, Huang DT, "et al" |title=Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations |journal=Nat. Genet. |volume=26 |issue=1 |pages=93–6 |year=2000 |month=September |pmid=10973257 |doi=10.1038/79246 |url=] cite journal |author=Crino P |title=New RELN Mutation Associated with Lissencephaly and Epilepsy |journal=Epilepsy Curr |volume=1 |issue=2 |pages=72 |year=2001 |month=November |pmid=15309195 |pmc=320825 |doi=10.1046/j.1535-7597.2001.00017.x |url=] 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. A novel chromosomal translocation causing the syndrome was described in 2007. cite journal |author=Zaki M, Shehab M, El-Aleem AA, "et al" |title=Identification of a novel recessive RELN mutation using a homozygous balanced reciprocal translocation |journal=Am. J. Med. Genet. A |volume=143A |issue=9 |pages=939–44 |year=2007 |month=May |pmid=17431900 |doi=10.1002/ajmg.a.31667 |url=] The mutations affecting reelin in human are usually associated with consanguineous marriage.

Schizophrenia

The factors mentioned above serve to corroborate the epigenetic hypothesis. But it is worth mentioning that in contrast with initial data, two recent studies have failed to confirm the RELN hypermethylation, cite journal |author=Tochigi M, Iwamoto K, Bundo M, Komori A, Sasaki T, Kato N, Kato T |title=Methylation Status of the Reelin Promoter Region in the Brain of Schizophrenic Patients |journal= Biological Psychiatry|volume= 63|issue= | pages = 530|year=2007 |pmid=17870056 |doi=10.1016/j.biopsych.2007.07.003] cite journal |author=Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L, Jia P, Assadzadeh A, Flanagan J, Schumacher A, Wang SC, Petronis A |title=Epigenomic profiling reveals DNA-methylation changes associated with major psychosis |journal=Am. J. Hum. Genet. |volume=82 |issue=3 |pages=696–711 |year=2008 |pmid=18319075 |doi=10.1016/j.ajhg.2008.01.008] and psychotropic medication could in itself affect the reelin expression in the brain, as animal studies show (see below).

Other interesting findings probably linking reelin pathway to developmental hypotheses of schizophrenia are noted in the studies on mice that are either prenatally infected with influenza virus cite journal | author = Fatemi SH, Emamian ES, Kist D, Sidwell RW, Nakajima K, Akhter P, Shier A, Sheikh S, Bailey K | title = Defective corticogenesis and reduction in Reelin immunoreactivity in cortex and hippocampus of prenatally infected neonatal mice | journal = Mol. Psychiatry | volume = 4 | issue = 2 | pages = 145–54 | year = 1999 | month = March | pmid = 10208446 | url = | doi = 10.1038/sj.mp.4000520 ] or have their immune system activated artificially during pregnancy. cite journal |author=Meyer U, Nyffeler M, Yee BK, Knuesel I, Feldon J |title=Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice |journal=Brain Behav Immun |volume= 22|issue= |pages= 469|year=2007 |pmid=18023140 |doi=10.1016/j.bbi.2007.09.012] The Cajal-Retzius cells in the newborns secrete significantly less reelin despite keeping their expression of calretinin and nNos within normal range. These data run in parrallel with the findings of increased risk of schizophrenia in humans after a prenatal infection during the second trimester.

Chromosome region 7q22 that harbours the "RELN" gene is associated with schizophrenia, cite journal |author=Wedenoja J, Loukola A, Tuulio-Henriksson A, Paunio T, Ekelund J, Silander K, Varilo T, Heikkilä K, Suvisaari J, Partonen T, Lönnqvist J, Peltonen L |title=Replication of linkage on chromosome 7q22 and association of the regional Reelin gene with working memory in schizophrenia families |journal= Mol Psychiatry |volume= 13|issue= |pages= 673|year=2007 |pmid=17684500 |doi=10.1038/sj.mp.4002047] and the gene itself was associated with the disease in a large study that found the polymorphism rs7341475 to increase the risk of the disease in women, but not in men. The women that have the SNP are about 1.4 times more likely to get ill, according to the study. cite journal |author=Shifman S, Johannesson M, Bronstein M, Chen SX, Collier DA, Craddock NJ, Kendler KS, Li T, O'Donovan M, O'Neill FA, Owen MJ, Walsh D, Weinberger DR, Sun C, Flint J, Darvasi A |title=Genome-Wide Association Identifies a Common Variant in the Reelin Gene That Increases the Risk of Schizophrenia Only in Women |journal=PLoS Genet. |volume=4 |issue=2 |pages=e28 |year=2008 |pmid=18282107 |doi=10.1371/journal.pgen.0040028 [http://genetics.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pgen.0040028 free full text] ] Allelic variations of RELN have also been correlated with working memory, memory and executive functioning in nuclear families where one of the members suffers from schizophrenia.

One study showed that patients have decreased levels of one of reelin receptors, VLDLR, in the peripheral lymphocytes. cite journal |author=Suzuki K, Nakamura K, Iwata Y, Sekine Y, Kawai M, Sugihara G, Tsuchiya KJ, Suda S, Matsuzaki H, Takei N, Hashimoto K, Mori N |title=Decreased expression of reelin receptor VLDLR in peripheral lymphocytes of drug-naive schizophrenic patients |journal= Schizophrenia Research|volume= 98|issue= |pages= 148|year=2007 |pmid=17936586 |doi=10.1016/j.schres.2007.09.029] After six months of antipsychotic therapy the expression went up; according to authors, peripheral VLRLR levels may serve as a reliable peripheral biomarker of schizophrenia.

Reelin pathway could also be linked to schizophrenia and other psychotic disorders through its interaction with risk genes. One example is the neuronal transcription factor NPAS3, disruption of which is linked to schizophrenia cite journal | author = Kamnasaran D, Muir WJ, Ferguson-Smith MA, Cox DW | title = Disruption of the neuronal PAS3 gene in a family affected with schizophrenia | journal = J. Med. Genet. | volume = 40 | issue = 5 | pages = 325–32 | year = 2003 | month = May | pmid = 12746393 | pmc = 1735455 | doi = 10.1136/jmg.40.5.325 | url = | issn = ] and learning disability. Knockout mice lacking NPAS3 or the similar protein NPAS1 have significantly lower levels of reelin; cite journal | author = Erbel-Sieler C, Dudley C, Zhou Y, "et al" | title = Behavioral and regulatory abnormalities in mice deficient in the NPAS1 and NPAS3 transcription factors | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 37 | pages = 13648–53 | year = 2004 | month = September | pmid = 15347806 | pmc = 518807 | doi = 10.1073/pnas.0405310101 | url = | issn = ] the precise mechanism leading to this is unknown. Another example is the schizophrenia-linked gene MTHFR, with murine knockouts showing decreased levels of reelin in the cerebellum. cite journal |author=Chen Z, Schwahn BC, Wu Q, He X, Rozen R |title=Postnatal cerebellar defects in mice deficient in methylenetetrahydrofolate reductase |journal=Int. J. Dev. Neurosci. |volume=23 |issue=5 |pages=465–74 |year=2005 |month=August |pmid=15979267 |doi=10.1016/j.ijdevneu.2005.05.007 ] Along the same line, it is worth noting that the gene coding for the subunit NR2B that is presumably affected by reelin in the process of NR2B->NR2A developmental change of NMDA receptor composition, stands as one of the strongest risk gene candidates. [http://www.schizophreniaforum.org/res/sczgene/geneoverview.asp?geneid=135 Gene Overview of All Published Schizophrenia-Association Studies for GRIN2B] - Schizophrenia Gene Database.]

Bipolar disorder

Decrease in RELN expression with concurrent upregulation of DNMT1 is typical of bipolar disorder with psychosis, but is not characteristic of patients with major depression without psychosis, wich could speak of specific association of the change with psychoses. 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.

Autism

Temporal lobe epilepsy

Decreased reelin expression in the hippocampal tissue samples from patients with temporal lobe epilepsy was found to be directly correlated with the extent of granule cell dispersion, a major feature of the disease that is noted in 45%-73% of patients. cite journal |author=Haas CA, Dudeck O, Kirsch M, "et al" |title=Role for reelin in the development of granule cell dispersion in temporal lobe epilepsy |journal=J. Neurosci. |volume=22 |issue=14 |pages=5797–802 |year=2002 |month=July |pmid=12122039 |doi=20026621 |url= |doi_brokendate=2008-07-08] cite journal |author=Heinrich C, Nitta N, Flubacher A, "et al" |title=Reelin deficiency and displacement of mature neurons, but not neurogenesis, underlie the formation of granule cell dispersion in the epileptic hippocampus |journal=J. Neurosci. |volume=26 |issue=17 |pages=4701–13 |year=2006 |month=April |pmid=16641251 |doi=10.1523/JNEUROSCI.5516-05.2006 |url=] 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. cite journal |author=Gong C, Wang TW, Huang HS, Parent JM |title=Reelin regulates neuronal progenitor migration in intact and epileptic hippocampus |journal=J. Neurosci. |volume=27 |issue=8 |pages=1803–11 |year=2007 |month=February |pmid=17314278 |doi=10.1523/JNEUROSCI.3111-06.2007 |url=]

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.cite journal |author=Botella-López A, Burgaya F, Gavín R, "et al" |title=Reelin expression and glycosylation patterns are altered in Alzheimer's disease |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=14 |pages=5573–8 |year=2006 |month=April |pmid=16567613 |pmc=1414634 |doi=10.1073/pnas.0601279103 |url=] This finding is in agreement with an earlier study showing the presence of Reelin associated with amyloid plaques in a transgenic AD mouse model.cite journal |author=Wirths O, Multhaup G, Czech C, "et al" |title=Reelin in plaques of beta-amyloid precursor protein and presenilin-1 double-transgenic mice |journal=Neurosci. Lett. |volume=316 |issue=3 |pages=145–8 |year=2001 |month=December |pmid=11744223|url= |doi=10.1016/S0304-3940(01)02399-0] A large genetic study of 2008 showed that RELN gene variation is associated with an increased risk of Alzheimer's disease in women. cite journal |author=Seripa D, Matera MG, Franceschi M, "et al" |title=The RELN locus in Alzheimer's disease |journal=J. Alzheimers Dis. |volume=14 |issue=3 |pages=335–44 |year=2008 |month=July |pmid=18599960 |url=http://iospress.metapress.com/openurl.asp?genre=article&issn=1387-2877&volume=14&issue=3&spage=335] The number of reelin-producing Cajal-Retzius cells is significantly decreased in first cortical layer of patients. cite journal |author=Baloyannis SJ |title=Morphological and morphometric alterations of Cajal-Retzius cells in early cases of Alzheimer's disease: a Golgi and electron microscope study |journal=Int. J. Neurosci. |volume=115 |issue=7 |pages=965–80 |year=2005 |month=July |pmid=16051543 |doi=10.1080/00207450590901396 |url=] cite journal |author=Baloyannis SJ, Costa V, Mauroudis I, Psaroulis D, Manolides SL, Manolides LS |title=Dendritic and spinal pathology in the acoustic cortex in Alzheimer's disease: morphological and morphometric estimation by Golgi technique and electron microscopy |journal=Acta Otolaryngol. |volume=127 |issue=4 |pages=351–4 |year=2007 |month=April |pmid=17453452 |doi=10.1080/00016480601126986 ] Some authors consider the reelin pathway to be a link between the Alzheimer's disease and schizophrenia. Aoki, Takeya; Mizuki, Yasushi; Terashima, Toshio [http://www.ingentaconnect.com/content/bsc/psy/2005/00000005/00000002/art00007 Relation between schizophrenia and Alzheimer's disease: the reelin signaling pathway] Psychogeriatrics, Volume 5, Number 2, June 2005 , pp. 42-47(6)]

Cancer

DNA methylation patterns are often changed in tumours, and RELN gene could be affected: according to one study, in the pancreatic cancer the expression is suppressed, along with other reelin pathway components. Sato N, Fukushima N, Chang R, Matsubayashi H, Goggins M. (2006) "Differential and epigenetic gene expression profiling identifies frequent disruption of the RELN pathway in pancreatic cancers." Gastroenterology. 130(2):548-65. PMID 16472607] On the contrary, in prostate cancer the RELN expression is excessive and correlates with Gleason score. Perrone G, Vincenzi B, Zagami M, Santini D, Panteri R, Flammia G, Verzi A, Lepanto D, Morini S, Russo A, Bazan V, Tomasino RM, Morello V, Tonini G, Rabitti C. (2007) "Reelin expression in human prostate cancer: a marker of tumor aggressiveness based on correlation with grade." Modern Pathology. doi:10.1038/modpathol.3800743. PMID 17277764] Retinoblastoma presents another example of RELN overexpression. cite journal |author=Seigel GM, Hackam AS, Ganguly A, Mandell LM, Gonzalez-Fernandez F |title=Human embryonic and neuronal stem cell markers in retinoblastoma |journal=Mol. Vis. |volume=13 |issue= |pages=823–32 |year=2007 |pmid=17615543 |url=http://www.molvis.org/molvis/v13/a90/]

Psychotropic medication and reelin expression

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.

According to the epigenetic hypothesis, drugs that shift the balance in favour of demethylation have a potential to alleviate the proposed methylation-caused downregulation of RELN and GAD67. In one study, closapine and sulpiride but not haloperidol and olanzapine were shown to increase the demethylation of both genes in mice pretreated with l-methionine. cite journal |author=Dong E, Nelson M, Grayson DR, Costa E, Guidotti A |title=Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation |journal=Proc. Natl. Acad. Sci. U.S.A. |volume= |issue= |pages= |year=2008 |month=August |pmid=18757738 |doi=10.1073/pnas.0805493105 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=18757738] Valproic acid, a histone deacetylase inhibitor, when taken in combination with antipsychotics, is proposed to have some benefits. But there are studies conflicting the main premise of the epigenetic hypothesis, and a study by Fatemi et al shows no increase in RELN expression by valproic acid; that indicates the need for further investigation.

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 of the following drugs:

References

Recommended reading

External links

Articles, publications, webpages

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* [http://www.wikigenes.org/e/gene/e/5649.html Human RELN at WikiGenes]

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