Disease relevance of RELN

• One of the genes identified, RELN (Reelin), a key regulator of neuronal migration, is frequently silenced in pancreatic cancers, as are several of its downstream mediators [1].
• Autosomal recessive lissencephaly with cerebellar hypoplasia, accompanied by severe delay, hypotonia, and seizures, has been associated with mutations of the reelin (RELN) gene [2].
• In the retina of embryos and alevins, RELN immunoreactivity is detected in cells of the ganglion cell layer (GCL) and inner nuclear layer (INL), and in the inner plexiform layer (IPL), where it appears as "diffuse" material confined to the ON-sublayer [3].
• In one family, the association of cortical dysplasia and congenital lymphedema have been related to mutations in the RELN gene [4].
• Here, we have analysed two major components of the reelin pathway involved in neuronal migration and cortical development, that is, p35 and disabled-1 (dab1), in gangliogliomas [5].

Psychiatry related information on RELN

• RESULTS: Prefrontal cortex and cerebellar expression of RELN mRNA, GAD(67) protein and mRNA, and prefrontal cortex RELN-positive cells was significantly decreased by 30% to 50% in patients with schizophrenia or bipolar disorder with psychosis, but not in those with unipolar depression without psychosis when compared with nonpsychiatric subjects [6].
• In all of the brain areas studied, RELN and its mRNA were significantly reduced (approximately 50%) in patients with schizophrenia; this decrease was similar in patients affected by undifferentiated or paranoid schizophrenia [7].
• Our findings suggest that longer triplet repeats in the 5'UTR of the RELN gene confer vulnerability to autistic disorder [8].
• Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study [6].
• Altered levels of cerebrospinal fluid reelin in frontotemporal dementia and Alzheimer's disease [9].

High impact information on RELN

• Role of the reelin signaling pathway in central nervous system development [10].
• The reeler phenotype thus seems to reflect a failure of early events associated with brain lamination which are normally controlled by reelin [11].
• Apoer2: a reelin receptor to remember [12].
• Moreover, a number of studies indicate that CR cells, and their secreted gene product, reelin, are involved in neuronal migration by acting on two key partners, migrating neurons and radial glial cells [13].
• Increased cell motility was also induced by knockdown of downstream components of the RELN pathway, including ApoER2, VLDLR, and DAB1 [1].

Chemical compound and disease context of RELN

• Treatment of pancreatic cancer cells with histone deacetylase inhibitors, valproic acid and suberoylanilide hydroxamic acid, restored the expression of RELN and DAB1 and markedly inhibited their migration [1].
• Hence, the increased expression of S-adenosyl methionine and DNA methyltransferase-1 may contribute to promoter cytosine 5-methylation and to downregulation of the expression of mRNAs encoding for reelin and GAD67 in cortical GABAergic neurons of schizhophrenia and bipolar disorder patients [14].
• The reelin signaling and tuberin/insulin growth receptor pathways have recently been implicated in ganglioglioma development [15].

Biological context of RELN

• Differential and epigenetic gene expression profiling identifies frequent disruption of the RELN pathway in pancreatic cancers [1].
• Importantly, small interfering RNA-mediated knockdown of RELN in pancreatic cancer cells that retain RELN expression resulted in greatly enhanced cell motility, invasiveness, and colony-forming ability [1].
• We further determined the cellular expression of the proteins RELN and DAB1 in 50 human brains ranging in age from 10 gestational weeks (GW) to 62 years using immunochemistry [16].
• We genotyped all four WNT2 polymorphisms and a polymorphic trinucleotide repeat in the 5' UTR of RELN in 107 families with multiple autistic children, and evaluated evidence for association between these variants and autism by the transmission disequilibrium test (TDT) [17].
• Our interpretation of these findings is that it is unlikely that DNA variations in RELN and WNT2 play a significant role in the genetic predisposition to autism [17].

Anatomical context of RELN

• RELN mRNA was preferentially expressed in GABAergic interneurons of PFC, temporal cortex, hippocampus, and glutamatergic granule cells of cerebellum [7].
• We found that Reln is expressed predominantly in layer I of both cortices and is localized to bitufted (double-bouquet), horizontal, and multipolar gamma-aminobutyric acid-ergic interneurons, which secrete Reln into extracellular matrix [18].
• Colocalization of integrin receptors and reelin in dendritic spine postsynaptic densities of adult nonhuman primate cortex [18].
• Expression and localization of reelin in human odontoblasts [19].
• This alternative reelin is generally expressed in the same cells as the major form, but is almost undetectable in retina and spinal cord [20].

Associations of RELN with chemical compounds

• In addition, the mRNA encoding the methylating enzyme, DNA methyltransferase 1, is up-regulated in the same neurons that coexpress reelin and glutamic acid decarboxylase 67 [21].
• The histone deacetylase inhibitors trichostatin A (TSA) and valproic acid also induced expression of the endogenous reelin promoter, although TSA was considerably more potent [22].
• RA-induced differentiation was also associated with demethylation of the reelin promoter [22].
• Retinoic acid (RA)-induced differentiation of NT2 cells to hNT neurons was accompanied by increased reelin expression and by the appearance of three DNase I hypersensitive sites 5' to the RNA start site [22].
• Here, we review the molecular mechanisms through which APOE, cholesterol, reelin and APOE receptors control synaptic functions that are essential for cognition, learning, memory, behaviour and neuronal survival [23].

Physical interactions of RELN

• We examined the expression of DISC1 and these selected binding partners as well as reelin, a protein in a related signaling pathway, in the hippocampus and dorsolateral prefrontal cortex of postmortem human brain patients with schizophrenia and controls [24].

Regulatory relationships of RELN

• The medial and dorsal cortical plate and Purkinje cells were reelin-negative but expressed disabled-1 (Dab1) mRNA [25].
• Our studies show that alterations in chromatin remodeling related to a selective upregulation of DNA-5-cytosine methyltransferase (DNMT) expression in GABAergic neurons of SZ PFC may induce a hypermethylation of reelin and GAD67 promoter CpG islands, which downregulates their expression [26].

Other interactions of RELN

• In the same samples of temporal cortex, we found a decrease in RELN protein of approximately 50% but no changes in DAB1 protein expression [7].
• CONCLUSIONS: The high prevalence of the silencing of RELN pathway components and its reversal by histone deacetylase inhibitors suggest the importance of this pathway as a diagnostic and therapeutic target for pancreatic cancer [1].
• Group differences were absent for DAB1,GAD(65) and neuron-specific-enolase expression implying that RELN and GAD(67) down-regulations were unrelated to neuronal damage [6].
• CONCLUSIONS: Reductions in Reelin protein and mRNA and Dab 1 mRNA and elevations in Reln receptor VLDLR mRNA demonstrate impairments in the Reelin signaling system in autism, accounting for some of the brain structural and cognitive deficits observed in the disorder [27].
• Tests for association in Duke and AGRE families were also performed on four additional SNPs in the genes PSMC2 and ORC5L, which flank RELN [28].

Analytical, diagnostic and therapeutic context of RELN

• RELN was mapped to human chromosome 7q22, based on both fluorescence in situ hybridization studies and localization within a well-positioned yeast artificial chromosome (YAC) contig [29].
• Screening RELN for DNA changes identified novel missense variants absent in a large control group; however, the low frequency of these mutations does not explain the relatively strong linkage results on 7q [30].
• Co-cultures of rat trigeminal ganglion (TG) and odontoblasts allow to mimic odontoblast innervation and demonstrate that neurites contact these cells with reelin molecules as observed in vivo in human dental pulp [19].
• The development of RELN immunoreactivity in the retina and the optic tectum of the brown trout are analyzed with a monoclonal (142) antibody against RELN whose suitability has been ascertained by western blot [3].
• We also found an inverse relationship between the level of DNA methylation using MSP analysis and the expression of the RELN gene using semi-quantitative RT-PCR [31].

References