leads to phosphorylation of actin-interacting protein cofilin 1 at ser3; this may stabilize the actin cytoskeleton and anchor the leading processes of migrating neuroblasts, preventing their further growth. interaction with cdk5 cyclin-dependent kinase 5 (cdk5), a major regulator of neuronal migration and positioning, is known to phosphorylate dab1 and other cytosolic targets of reelin signaling, such as tau, which could be activated also via reelin-induced deactivation of gsk3b, and nudel, associated with lis1, one of the dab1 targets. ltp induction by reelin in hippocampal slices fails in p35 knockouts. p35 is a key cdk5 activator, and double p35/dab1, p35/reln, p35/apoer2, p35/vldlr knockouts display increased neuronal migration deficits, indicating a synergistic action of reelin → apoer2/vldlr → dab1 and p35/p39 → cdk5 pathways in the normal corticogenesis. possible pathological role lissencephaly disruptions of the reln gene are considered to be the cause of the rare form of lissencephaly with cerebellar hypoplasia classed as a microlissencephaly called norman-roberts syndrome. the mutations disrupt splicing of the reln mrna transcript, 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 are also present. a novel chromosomal translocation causing the syndrome was described in 2007. schizophrenia reduced expression of reelin and its mrna levels in the brains of schizophrenia sufferers had been reported in 1998 and 2000, and independently confirmed in postmortem studies of the hippocampus, cerebellum, basal ganglia, and cerebral cortex. the reduction may reach up to 50% in some brain regions and is coupled with reduced expression of gad-67 enzyme, which catalyses the transition of glutamate to gaba. blood levels of reelin and its isoforms are also altered in schizophrenia, along with mood disorders, according to one study. 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. epigenetic hypermethylation of dna in schizophrenia patients is proposed as a cause of the reduction, in agreement with the observations dating from the 1960s that administration of methionine to schizophrenic patients results in a profound exacerbation of schizophrenia symptoms in sixty to seventy percent of patients. the proposed mechanism is a part of the "epigenetic hypothesis for schizophrenia pathophysiology" formulated by a group of scientists in 2008 (d. grayson; a. guidotti; e. costa). a postmortem study comparing a dna methyltransferase (dnmt1) and reelin mrna expression in cortical layers i and v of schizophrenic patients and normal controls demonstrated that in the layer v both dnmt1 and reelin levels were normal, while in the layer i dnmt1 was threefold higher, probably leading to the twofold decrease in the reelin expression. there is evidence that the change is selective, and dnmt1 is overexpressed in reelin-secreting gabaergic neurons but not in their glutamatergic neighbours. methylation inhibitors and histone deacetylase inhibitors, such as valproic acid, increase reelin mrna levels, while l-methionine treatment downregulates the phenotypic expression of reelin. one study indicated the upregulation of histone deacetylase hdac1 in the hippocampi of patients. histone deacetylases suppress gene promoters; hyperacetylation of histones was shown in murine models to demethylate the promoters of both reelin and gad67. dnmt1 inhibitors in animals have been shown to increase the expression of both reelin and gad67, and both dnmt inhibitors and hdac inhibitors shown in one study to activate both genes with comparable dose- and time-dependence. as one study shows, s-adenosyl methionine (sam) concentration in patients' prefrontal cortex is twice as high as in the cortices of non-affected people. sam, being a methyl group donor necessary for dnmt activity, could further shift epigenetic control of gene expression. chromosome region 7q22 that harbours the reln gene is associated with schizophrenia, 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 single-nucleotide polymorphism (snp) are about 1.4 times more likely to get ill, according to the study. 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. the association with working memory was later replicated. in one small study, nonsynonymous polymorphism val997leu of the gene was associated with left and right ventricular enlargement in patients. one study showed that patients have decreased levels of one of reelin receptors, vldlr, in the peripheral lymphocytes. 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. considering the role of reelin in promoting dendritogenesis, suggestions were made that the localized dendritic spine deficit observed in schizophrenia could be in part connected with the downregulation of reelin. 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 and learning disability. knockout mice lacking npas3 or the similar protein npas1 have significantly lower levels of reelin; the precise mechanism behind this is unknown. another example is the schizophrenia-linked gene mthfr, with murine knockouts showing decreased levels of reelin in the cerebellum. 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. another shared aspect between nr2b and reln is that they both can be regulated by the tbr1 transcription factor. the heterozygous reeler mouse, which is haploinsufficient for the reln gene, shares several neurochemical and behavioral abnormalities with schizophrenia and bipolar disorder, but the exact relevance of these murine behavioral changes to the pathophysiology of schizophrenia remains debatable. as previously described, reelin plays a crucial role in modulating early neuroblast migration during brain development. evidences of altered neural cell positioning in post-mortem schizophrenia patient brains and changes to gene regulatory networks that control cell migration suggests a potential link between altered reelin expression in patient brain tissue to disrupted cell migration during brain development. to model the role of reelin in the context of schizophrenia at a cellular level, olfactory neurosphere-derived cells were generated from the nasal biopsies of schizophrenia patients, and compared to cells from healthy controls. schizophrenia patient-derived cells have reduced levels of reelin mrna and protein when compared to healthy control cells, but expresses the key reelin receptors and dab1 accessory protein. when grown in vitro, schizophrenia patient-derived cells were unable to respond to reelin coated onto tissue culture surfaces; in contrast, cells derived from healthy controls were able to alter their cell migration when exposed to reelin. this work went on to show that the lack of cell migration response in patient-derived cells were caused by the cell's inability to produce enough focal adhesions of the appropriate size when in contact with extracellular reelin. more research into schizophrenia cell-based models are needed to look at the function of reelin, or lack of, in the pathophysiology of schizophrenia. bipolar disorder decrease in reln expression with concurrent upregulation of dnmt1 is typical of bipolar disorder with psychosis, but is not characteristic of patients with major depression without psychosis, which could speak of specific association of the change with psychoses. 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. in a genetic study conducted in 2009, preliminary evidence requiring further dna replication suggested that variation of the reln gene (snp rs362719) may be associated with susceptibility to bipolar disorder in women. autism main article: heritability of autism autism is a neurodevelopmental disorder that is generally believed to be caused by mutations in several locations, likely triggered by environmental factors. the role of reelin in autism is not decided yet. reelin was originally in 2001 implicated in a study finding associations between autism and a polymorphic ggc/cgg repeat preceding the 5' atg initiator codon of the reln gene in an italian population. longer triplet repeats in the 5' region were associated with an increase in autism susceptibility. however, another study of 125 multiple-incidence families and 68 single-incidence families from the subsequent year found no significant difference between the length of the polymorphic repeats in affected and controls. although, using a family based association test larger reelin alleles were found to be transmitted more frequently than expected to affected children. an additional study examining 158 subjects with german lineage likewise found no evidence of triplet repeat polymorphisms associated with autism. and a larger study from 2004 consisting of 395 families found no association between autistic subjects and the cgg triplet repeat as well as the allele size when compared to age of first word. in 2010 a large study using data from 4 european cohorts would find some evidence for an association between autism and the rs362780 reln polymorphism. studies of transgenic mice have been suggestive of an association, but not definitive. temporal lobe epilepsy: granule cell dispersion 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 (gcd), a major feature of the disease that is noted in 45%–73% of patients. the dispersion, according to a small study, is associated with the reln promoter hypermethylation. 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. moreover, in a kainate-induced mouse epilepsy model, exogenous reelin had prevented gcd, according to one study. alzheimer's disease the reelin receptors apoer2 and vldlr belong to the ldl receptor gene family. all members of this family are receptors for apolipoprotein e (apoe). therefore, they are often synonymously referred to as 'apoe receptors'. apoe occurs in 3 common isoforms (e2, e3, e4) in the human population. apoe4 is the primary genetic risk factor for late-onset alzheimer's disease. this strong genetic association has led to the proposal that apoe receptors play a central role in the pathogenesis of alzheimer's disease. 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. this finding is in agreement with an earlier study showing the presence of reelin associated with amyloid plaques in a transgenic ad mouse model. a large genetic study of 2008 showed that reln gene variation is associated with an increased risk of alzheimer's disease in women. the number of reelin-producing cajal-retzius cells is significantly decreased in the first cortical layer of patients. reelin has been shown to interact with amyloid precursor protein, and, according to one in-vitro study, is able to counteract the aβ-induced dampening of nmda-receptor activity. this is modulated by apoe isoforms, which selectively alter the recycling of apoer2 as well as ampa and nmda receptors. cancer dna methylation patterns are often changed in tumours, and the reln gene could be affected: according to one study, in the pancreatic cancer the expression is suppressed, along with other reelin pathway components in the same study, cutting the reelin pathway in cancer cells that still expressed reelin resulted in increased motility and invasiveness. on the contrary, in prostate cancer the reln expression is excessive and correlates with gleason score. retinoblastoma presents another example of reln overexpression. this gene has also been seen recurrently mutated in cases of acute lymphoblastic leukaemia. other conditions one genome-wide association study indicates a possible role for reln gene variation in otosclerosis, an abnormal growth of bone of the middle ear. in a statistical search for the genes that are differentially expressed in the brains of cerebral malaria-resistant versus cerebral malaria-susceptible