Disabled-1 Research Articles

Novel genotype–phenotype correlations, differential cerebellar allele-specific methylation, and a common origin of the (ATTTC)n insertion in spinocerebellar ataxia type 37

Spinocerebellar ataxia subtype 37 (SCA37) is a rare disease originally identified in ataxia patients from the Iberian Peninsula with a pure cerebellar syndrome. SCA37 patients carry a pathogenic intronic (ATTTC)n repeat insertion flanked by two polymorphic (ATTTT)n repeats in the Disabled-1 (DAB1) gene leading to cerebellar dysregulation. Herein, we determine the precise configuration of the pathogenic 5ʹ(ATTTT)n–(ATTTC)n–3ʹ(ATTTT)n SCA37 alleles by CRISPR–Cas9 and long-read nanopore sequencing, reveal their epigenomic signatures in SCA37 lymphocytes, fibroblasts, and cerebellar samples, and establish new molecular and clinical correlations. The 5ʹ(ATTTT)n–(ATTTC)n–3ʹ(ATTTT)n pathogenic allele configurations revealed repeat instability and differential methylation signatures. Disease age of onset negatively correlated with the (ATTTC)n, and positively correlated with the 3ʹ(ATTTT)n. Geographic origin and gender significantly correlated with age of onset. Furthermore, significant predictive regression models were obtained by machine learning for age of onset and disease evolution by considering gender, the (ATTTC)n, the 3ʹ(ATTTT)n, and seven CpG positions differentially methylated in SCA37 cerebellum. A common 964-kb genomic region spanning the (ATTTC)n insertion was identified in all SCA37 patients analysed from Portugal and Spain, evidencing a common origin of the SCA37 mutation in the Iberian Peninsula originating 859 years ago (95% CI 647–1378). In conclusion, we demonstrate an accurate determination of the size and configuration of the regulatory 5ʹ(ATTTT)n–(ATTTC)n–3ʹ(ATTTT)n repeat tract, avoiding PCR bias amplification using CRISPR/Cas9-enrichment and nanopore long-read sequencing, resulting relevant for accurate genetic diagnosis of SCA37. Moreover, we determine novel significant genotype–phenotype correlations in SCA37 and identify differential cerebellar allele-specific methylation signatures that may underlie DAB1 pathogenic dysregulation.

M6A Methylation-Mediated Stabilization of LINC01106 Suppresses Bladder Cancer Progression by Regulating the miR-3148/DAB1 Axis.

The pivotal roles of long noncoding RNAs (lncRNAs) in the realm of cancer biology, inclusive of bladder cancer (BCa), have been substantiated through various studies. Remarkably, RNA methylation, especially m6A modification, has demonstrated its influence on both coding and noncoding RNAs. Nonetheless, the explicit impact of RNA methylation on lncRNAs and its subsequent contribution to the progression of BCa remains to be elucidated. In the present investigation, we scrutinized the expression and m6A methylation status of LINC01106, employing quantitative real-time PCR (qRT-PCR) and methylated RNA immunoprecipitation (MeRIP)-qPCR. To decipher the regulatory mechanism underpinning LINC01106, we utilized RNA immunoprecipitation (RIP)-qPCR, methylated RNA immunoprecipitation (MeRIP) assays, and bioinformatic analysis. Furthermore, the CRISPR/dCas13b-METTL3-METTL14 system was implemented to probe the function of LINC01106. The findings of our study indicated that LINC01106 is under expressed and exhibits diminished m6A methylation levels in BCa tissues when compared those of normal controls. A diminished expression of LINC01106 was associated with a less favorable prognosis in BCa patients. Intriguingly, CRISPR-mediated hypermethylation of LINC01106, facilitated by dCas13b-M3-M14, abolished the malignant phenotype of the BCa cells, an effect that could be inverted by Disabled-1 (DAB1) knockdown. From a mechanistic standpoint, we identified an m6A modification site on LINC01106 and highlighted YTHDC1 as a potential reader protein implicated in this process. Additionally, a positive correlation between DAB1 and LINC01106 expression was observed, with miR-3148 potentially acting as a mediator in this relationship. In summary, our research unveils a suppressive regulatory role of the LINC01106/miR-3148/DAB1 axis in the progression of BCa and underscores the YTHDC1-mediated m6A modification mechanism in regards to LINC01106. These revelations propose a new therapeutic target for the management of BCa.

CNSC-34. BAF60C/SMARCD3 MODULATES CEREBELLUM DEVELOPMENT AND MEDULLOBLASTOMA METASTASIS

Abstract Medulloblastoma (MB), the most common type of embryonal tumor in children, is a fast-growing and heterogeneous brain tumor arising in the cerebellum. The molecular characterization of MB reveals four major subgroups (WNT, SHH, Group 3, and Group 4) and Group 3 is the most aggressive and malignant, characterized by frequent metastasis at diagnosis and the worst prognosis. We have recently found that BAF60C/SMARCD3 is highly expressed in Group 3 MB and associated with poor prognosis. Mechanistically, BAF60C/SMARCD3 hijacks a neurodevelopmental epigenetic program mediated by Disabled1 (DAB1)-Reelin signaling to promote metastatic dissemination in MB. Using single-cell RNA sequencing data of developing mouse and human cerebellum, we found that BAF60C/SMARCD3 expression in Purkinje cells (PCs) is upregulated during embryonic and early postnatal stages, but downregulated during the late postnatal stage of cerebellar development. To examine the effect of BAF60C/SMARCD3 depletion on PC migration and positioning during embryonic and postnatal stages of cerebellar development, we generated targeted knockout mice by crossing the PC-specific Cre mouse (L7Cre-2 and FoxP2-Cre) with the Smarcd3flox/flox mouse. We found that BAF60C/SMARCD3 depletion significantly influences embryo development in FoxP2-Cre; Smarcd3flox/flox but not in L7Cre-2; Smarcd3flox/flox mice, further supporting the expression of BAF60C/SMARCD3 in early stage (Foxp2 +) but not in the late stage (L7/Pcp2+) during cerebellum development. To determine whether BAF60C/SMARCD3 contributes to MB development, we injected lentivirus-carrying constitutively active MYCS62D with/without BAF60C/SMARCD3 in C57BL/6J mice. Interestingly, we found that MYCS62D with BAF60C/SMARCD3 can induce a spontaneous Group3-like MB with strong metastatic dissemination compared to MYCS62D without BAF60C/SMARCD3. These results demonstrate that BAF60C/SMARCD3 plays a pivotal role in PC biology and cerebellar development, and tumor cells hijack BAF60C/SMARCD3-Reelin signaling to promote tumor metastasis in MB.

Effect of in ovo feeding of folic acid on Disabled-1 and gga-miR-182-5p expression in the cerebral cortex of chick embryo.

Folate (vitamin B9) has been shown to reduce the prevalence of neural tube defects (NTDs). Many genes comprising Disabled-1 (DAB1) and miRNAs have been shown to play important role in normal brain development. Reelin-signalling has been shown to play key role in regulating of neuronal migration during brain development. The aim of this study was to evaluate the effects of in ovo administration of folic acid (FA) on DAB1 and gga-miR-182-5p expression in the cerebral cortex of chick embryo. A total number of 30 hatching eggs were used in this study. The number of 10 eggs were injected into the yolk sac with FA(150 µg/egg), 10 eggs by normal saline (sham group) on embryonic day 11 and 10 eggs were left without injection as control. Then the cerebral cortices were collected on E19 and the expression of DAB1 and gga-miR-182-5p was studied by Real-Time PCR. The results showed that DAB1 expression in the cerebral cortex of FA-treated, sham and control were 2.51 ± 0.13, 1.01 ± 0.04and 1.03 ± 0.04 fold changes, respectively, and this amount for gga-miR-182-5p were 0.54 ± 0.03, 1.09 ± 0.07 and 1.00 ± 0.06-fold changerespectively. Statistical analysis showed that there is a significant increase in DAB1 and a decrease in gga-miR-182-5p expression in FA injected cerebral cortex as compared either with either SHAM or control (p < 0.0001). But, no significant change in DAB1 and gga-miR-182-5p expression was observed between sham and the control group (p = 0.99 and p = 0.57respectively). It is concluded that in ovo feeding of FA increases DAB1 and decreases gga-miR-182-5p expression in the developing chick cerebral cortex.

TRIM40 ameliorates diabetic retinopathy through suppressing inflammation via Reelin/DAB1 signaling disruption: A mechanism by proteasomal degradation of DAB1

Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus. Reelin, an extracellular matrix protein, and its effector protein Disabled1 (DAB1) have been linked to cellular events and retinal development. However, whether and how Reelin/DAB1 signaling causes DR remains to be investigated. In our study, significantly increased expression of Reelin, very low density lipoprotein receptor (VLDLR), ApoE receptor 2 (ApoER2) and phosphorylated DAB1 in retinas of streptozotocin (STZ)-induced DR mouse model was observed, along with enhanced expression of proinflammatory factors. Similar results are confirmed in high glucose (HG)-treated human retinal pigment epithelium cell line ARPE-19. Surprisingly, dysregulated tripartite motif-containing 40 (TRIM40), an E3 ubiquitin ligase, is found to be involved in DR progression by bioinformatic analysis. We observe a negative correlation between TRIM40 and p-DAB1 protein expression levels under HG conditions. Importantly, we find that TRIM40 over-expression markedly ameliorates HG-induced p-DAB1, PI3K, p-protein B kinase (AKT) and inflammatory response in HG-treated cells, but dose not affect Reelin expression. Of note, Co-IP and double immunofluorescence identify an interaction between TRIM40 and DAB1. Furthermore, we show that TRIM40 enhances K48-linked polyubiquitination of DAB1, thereby promoting DAB1 degradation. Finally, promoting TRIM40 expression by intravenous injection of the constructed adeno-associated virus (AAV-TRIM40) markedly ameliorates DR phenotypes in STZ-treated mice, as indicated by the decreased blood glucose and glycosylated hemoglobin (HbAlc) levels, and increased hemoglobin contents. Additionally, diabetes-related elevation of acellular capillaries was also meliorated in mice over-expressing TRIM40. The electroretinogram (ERG) deficits were strongly rescued in mice receiving AAV-TRIM40 injection. Moreover, AAV-TRIM40 attenuates the inflammation and p-DAB1 expression in retinal tissues of STZ-treated mice. Collectively, our findings disclose a mechanism through which TRIM40 limits DAB1 stability under physiological conditions and reveals TRIM40 as a potential therapeutic target for the intervention of Reelin/DAB1 signaling, contributing to DR treatment.

A neurodevelopmental epigenetic programme mediated by SMARCD3–DAB1–Reelin signalling is hijacked to promote medulloblastoma metastasis

How abnormal neurodevelopment relates to the tumour aggressiveness of medulloblastoma (MB), the most common type of embryonal tumour, remains elusive. Here we uncover a neurodevelopmental epigenomic programme that is hijacked to induce MB metastatic dissemination. Unsupervised analyses of integrated publicly available datasets with our newly generated data reveal that SMARCD3 (also known as BAF60C) regulates Disabled 1 (DAB1)-mediated Reelin signalling in Purkinje cell migration and MB metastasis by orchestrating cis-regulatory elements at the DAB1 locus. We further identify that a core set of transcription factors, enhancer of zeste homologue 2 (EZH2) and nuclear factor I X (NFIX), coordinates with the cis-regulatory elements at the SMARCD3 locus to form a chromatin hub to control SMARCD3 expression in the developing cerebellum and in metastatic MB. Increased SMARCD3 expression activates Reelin–DAB1-mediated Src kinase signalling, which results in a MB response to Src inhibition. These data deepen our understanding of how neurodevelopmental programming influences disease progression and provide a potential therapeutic option for patients with MB.

Rare single-nucleotide DAB1 variants and their contribution to Schizophrenia and autism spectrum disorder susceptibility

Disabled 1 (DAB1) is an intracellular adaptor protein in the Reelin signaling pathway and plays an essential role in correct neuronal migration and layer formation in the developing brain. DAB1 has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in genetic, animal, and postmortem studies. Recently, increasing attention has been given to rare single-nucleotide variants (SNVs) found by deep sequencing of candidate genes. In this study, we performed exon-targeted resequencing of DAB1 in 370 SCZ and 192 ASD patients using next-generation sequencing technology to identify rare SNVs with a minor allele frequency <1%. We detected two rare missense mutations (G382C, V129I) and then performed a genetic association study in a sample comprising 1763 SCZ, 380 ASD, and 2190 healthy control subjects. Although no statistically significant association with the detected mutations was observed for either SCZ or ASD, G382C was found only in the case group, and in silico analyses and in vitro functional assays suggested that G382C alters the function of the DAB1 protein. The rare variants of DAB1 found in the present study should be studied further to elucidate their potential functional relevance to the pathophysiology of SCZ and ASD.

Inhibition of microRNA-300 inhibits cell adhesion, migration, and invasion of prostate cancer cells by promoting the expression of DAB1

ABSTRACT Prostate cancer (PC) is the most common malignancy in men. As per recent findings, microRNA-300 (miR-300) were found to be overexpressed in numerous types of cancers. In this study, we aimed to explore the effects of miR-300 on the adhesion, invasion, and migration of PC cells by targeting Disabled 1 (DAB1). Firstly, the regulatory role of miRNAs on DAB1 was predicted by screening PC-related differentially expressed genes (DEGs). Immunohistochemistry was applied to determine the positive protein expression of DAB1, after which the target relationship between miR-300 and DAB1 was examined. Loss-of-function and gain-of-function experiments were conducted to determine cell proliferation, adhesion, migration, invasion capability, and cell cycle of PC cells. Our data illustrated that DAB1 had a low expression, while miR-300 was expressed at a relatively high level in PC tissues. Moreover, our clinicopathological analysis revealed that there was a correlation between miR-300 and tumor, node, metastases stage, Gleason score, and lymph node metastasis of PC patients. DAB1 was also found to be poorly expressed in PC based on the findings from the microarray analysis. The results from dual-luciferase reporter gene assay corroborated that miR-300 interacts with DAB1. Importantly, overexpression of miR-300 and/or si-DAB1 resulted in the enhancement of RAC1, MMP2, MMP9, CyclinD1, and CyclinE expressions, whereas the expression of DAB1 and Rap was reduced in PC cells, thus suggesting that down-regulated miR-300 suppressed proliferation, adhesion, migration, and invasion of PC cells. Collectively, our results provided evidence that down-regulation of miR-300 inhibits the adhesion, migration, and invasion of PC cells.

Assessment of expression of RELN signaling pathway in multiple sclerosis patients

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. Nearly 85% of MS patients are recognized with relapsing-remitting MS (RRMS), a typical clinical course of disease which is distinguished by several episodes of relapses, separated by remissions of neurological impairment. Failure of repair mechanisms is a main factor in progression of neurological dysfunction in MS. Several lines of evidence suggest that Reelin (RELN) signaling pathway can contribute in the regulation of repair mechanisms in MS patients. In the present study, we assessed expression levels of RELN and Disabled-1 (DAB1), two key genes in RELN signaling pathway, in peripheral blood of 50 RRMS patients and 50 matched healthy subjects. RELN was significantly down-regulated in total MS patients, and total female patients compared with the matched controls. However, no statistically significant difference was found in DAB1 mRNA expression between MS patients and controls. Furthermore, considerable correlations were detected between expression levels of RELN and DAB1 in the patients group. There were no significant correlations between expression levels of genes and EDSS, disease duration or age at onset. Our study provides evidences for the role of RELN signaling pathway in the pathogenesis of MS. Further studies are required to clarify the exact clinical significance of this pathway in MS patients.

Neurobehavioral performances and brain regional metabolism in Dab1scm (scrambler) mutant mice

As disabled-1 (DAB1) protein acts downstream in the reelin signaling pathway modulating neuronal migration, glutamate neurotransmission, and cytoskeletal function, the disabled-1 gene mutation (scrambler or Dab1scm mutation) results in ataxic mice displaying dramatic neuroanatomical defects similar to those observed in the reeler gene (Reln) mutation. By comparison to non-ataxic controls, Dab1scm mutants showed severe motor coordination impairments on stationary beam, coat-hanger, and rotorod tests but were more active in the open-field. Dab1scm mutants were also less anxious in the elevated plus-maze but with higher latencies in the emergence test. In mutants versus controls, changes in regional brain metabolism as measured by cytochrome oxidase (COX) activity occurred mainly in structures intimately connected with the cerebellum, in basal ganglia, in limbic regions, particularly hippocampus, as well as in visual and parietal sensory cortices. Although behavioral results characterized a major cerebellar disorder in the Dab1scm mutants, motor activity impairments in the open-field were associated with COX activity changes in efferent basal ganglia structures such as the substantia nigra, pars reticulata. Metabolic changes in this structure were also associated with the anxiety changes observed in the elevated plus-maze and emergence test. These results indicate a crucial participation of the basal ganglia in the functional phenotype of ataxic Dab1scm mutants.

Pancortins interact with amyloid precursor protein and modulate cortical cell migration

Neuronal precursor cell migration in the developing mammalian brain is a complex process requiring the coordinated interaction of numerous proteins. We have recently shown that amyloid precursor protein (APP) plays a role in migration into the cortical plate through its interaction with two cytosolic signaling proteins, disabled 1 (DAB1) and disrupted in schizophrenia 1 (DISC1). In order to identify extracellular factors that may signal through APP to regulate migration, we performed an unbiased mass spectrometry-based screen for factors that bind to the extracellular domain of APP in the rodent brain. Through this screen, we identified an interaction between APP and pancortins, proteins expressed throughout the developing and mature cerebral cortex. Via co-immunoprecipitation, we show that APP interacts with all four of the mammalian pancortin isoforms (AMY, AMZ, BMY, BMZ). We demonstrate that the BMZ and BMY isoforms of pancortin can specifically reduce β-secretase- but not α-secretase-mediated cleavage of endogenous APP in cell culture, suggesting a biochemical consequence of the association between pancortins and APP. Using in utero electroporation to overexpress and knock down specific pancortin isoforms, we reveal a novel role for pancortins in migration into the cortical plate. Interestingly, we observe opposing roles for alternate pancortin isoforms, with AMY overexpression and BMZ knock down both preventing proper migration of neuronal precursor cells. Finally, we show that BMZ can partially rescue a loss of APP expression and that APP can rescue effects of AMY overexpression, suggesting that pancortins act in conjunction with APP to regulate entry into the cortical plate. Taken together, these results suggest a biochemical and functional interaction between APP and pancortins, and reveal a previously unidentified role for pancortins in mammalian cortical development.

Interference with reelin signaling in the lateral entorhinal cortex impairs spatial memory

Entorhinal neurons receive extensive intracortical projections, and form the primary input to the hippocampus via the perforant pathway. The glutamatergic cells of origin for the perforant pathway are distinguished by their expression of reelin, a glycoprotein involved in learning and synaptic plasticity. The functional significance of reelin signaling within the entorhinal cortex, however, remains unexplored. To determine whether interrupting entorhinal reelin signaling might have consequences for learning and memory, we administered recombinant receptor-associated protein (RAP) into the lateral entorhinal cortex (LEC) of young Long-Evans rats. RAP prevents reelin from binding to its receptors, and we verified the knockdown of reelin signaling by quantifying the phosphorylation state of reelin’s intracellular signaling target, disabled-1 (DAB1). Effective knockdown of reelin signaling was associated with impaired performance in the hippocampus-dependent version of the water maze. Moreover, inhibition of reelin signaling induced a localized loss of synaptic marker expression in the LEC. These observations support a role for entorhinal reelin signaling in spatial learning, and suggest that an intact reelin signaling pathway is essential for synaptic integrity in the adult entorhinal cortex.

A role of Disable-1 as a transcription factor in Reelin signaling

As disabled-1 (DAB1) protein acts downstream in the reelin signaling pathway modulating neuronal migration, glutamate neurotransmission, and cytoskeletal function, the disabled-1 gene mutation (scrambler or Dab1scm mutation) results in ataxic mice displaying dramatic neuroanatomical defects similar to those observed in the reeler gene (Reln) mutation. By comparison to non-ataxic controls, Dab1scm mutants showed severe motor coordination impairments on stationary beam, coat-hanger, and rotorod tests but were more active in the open-field. Dab1scm mutants were also less anxious in the elevated plus-maze but with higher latencies in the emergence test. In mutants versus controls, changes in regional brain metabolism as measured by cytochrome oxidase (COX) activity occurred mainly in structures intimately connected with the cerebellum, in basal ganglia, in limbic regions, particularly hippocampus, as well as in visual and parietal sensory cortices. Although behavioral results characterized a major cerebellar disorder in the Dab1scm mutants, motor activity impairments in the open-field were associated with COX activity changes in efferent basal ganglia structures such as the substantia nigra, pars reticulata. Metabolic changes in this structure were also associated with the anxiety changes observed in the elevated plus-maze and emergence test. These results indicate a crucial participation of the basal ganglia in the functional phenotype of ataxic Dab1scm mutants.

Mouse Disabled1 (DAB1) Is a Nucleocytoplasmic Shuttling Protein

Disabled1 (DAB1) is an intracellular mediator of the Reelin-signaling pathway and essential for correct neuronal positioning during brain development. So far, DAB1 has been considered a cytoplasmic protein. Here, we show that DAB1 is subject to nucleocytoplasmic shuttling. In its steady state, DAB1 is mainly located in the cytoplasm. However, treatment with leptomycine B, a specific inhibitor of the CRM1 (chromosomal region maintenance 1)-RanGTP-dependent nuclear export, resulted in nuclear accumulation of DAB1. By using deletion or substitutional mutants of DAB1 fused with enhanced green fluorescent protein, we have mapped a bipartite nuclear localization signal and two CRM1-dependent nuclear export signals. These targeting signals were functional in both Neuro2a cells and primary cerebral cortical neurons. Using purified recombinant proteins, we have shown that CRM1 binds to DAB1 directly in a RanGTP-dependent manner. We also show that tyrosine phosphorylation of DAB1, which is indispensable for the layer formation of the brain, by Fyn tyrosine kinase or Reelin stimulation did not affect the subcellular localization of DAB1 in vitro. These results suggest that DAB1 is a nucleocytoplasmic shuttling protein and raise the possibility that DAB1 plays a role in the nucleus as well as in the cytoplasm.

The Gene Encoding Disabled-1 (DAB1), the Intracellular Adaptor of the Reelin Pathway, Reveals Unusual Complexity in Human and Mouse

The Disabled-1 (Dab1) gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. The DAB1 protein docks to the intracellular part of the Reelin very low density lipoprotein receptor and apoE receptor type 2 and becomes tyrosine-phosphorylated following binding of Reelin to cortical neurons. In mice, mutations of Dab1 and Reelin generate identical phenotypes. In humans, Reelin mutations are associated with brain malformations and mental retardation; mutations in DAB1 have not been identified. Here, we define the organization of Dab1, which is similar in human and mouse. The Dab1 gene spreads over 1100 kb of genomic DNA and is composed of 14 exons encoding the major protein form, some alternative internal exons, and multiple 5'-exons. Alternative polyadenylation and splicing events generate DAB1 isoforms. Several 5'-untranslated regions (UTRs) correspond to different promoters. Two 5'-UTRs (1A and 1B) are predominantly used in the developing brain. 5'-UTR 1B is composed of 10 small exons spread over 800 kb. With a genomic length of 1.1 Mbp for a coding region of 5.5 kb, Dab1 provides a rare example of genomic complexity, which will impede the identification of human mutations.

Interactions of the Low Density Lipoprotein Receptor Gene Family with Cytosolic Adaptor and Scaffold Proteins Suggest Diverse Biological Functions in Cellular Communication and Signal Transduction

The members of the low density lipoprotein (LDL) receptor gene family bind a broad spectrum of extracellular ligands. Traditionally, they had been regarded as mere cargo receptors that promote the endocytosis and lysosomal delivery of these ligands. However, recent genetic experiments in mice have revealed critical functions for two LDL receptor family members, the very low density lipoprotein receptor and the apoE receptor-2, in the transmission of extracellular signals and the activation of intracellular tyrosine kinases. This process regulates neuronal migration and is crucial for brain development. Signaling through these receptors requires the interaction of their cytoplasmic tails with the intracellular adaptor protein Disabled-1 (DAB1). Here, we identify an extended set of cytoplasmic proteins that might also participate in signal transmission by the LDL receptor gene family. Most of these novel proteins are adaptor or scaffold proteins that contain PID or PDZ domains and function in the regulation of mitogen-activated protein kinases, cell adhesion, vesicle trafficking, or neurotransmission. We show that binding of DAB1 interferes with receptor internalization suggesting a mechanism by which signaling through this class of receptors might be regulated. Taken together, these findings imply much broader physiological functions for the LDL receptor family than had previously been appreciated. They form the basis for the elucidation of the molecular pathways by which cells respond to the diversity of ligands that bind to these multifunctional receptors on the cell surface.

223. Reelin and GAD67 downregulation and psychosis vulnerability

Reelin (RELN) is an extracellular matrix (ECM) protein synthesized and released by GABAergic interneurons (horizontal, bitufted, Martinotti cells) in cortex. The interaction of RELN with a putative receptor domain of the ECM triggers an intracellular transduction cascade phosphorylating disabled1 (DAB1) which functions as an adaptor protein facilitating transfer to the nucleus of specific tyrosine kinases which may initiate gene transcription.