Autosomal Homologue Research Articles

An in-depth review of the function of RNA-binding protein FXR1 in neurodevelopment.

FMR1 autosomal homolog 1 (FXR1) is an RNA-binding protein that belongs to the Fragile X-related protein (FXR) family. FXR1 is critical for development, as its loss of function is intolerant in humans and results in neonatal death in mice. Although FXR1 is expressed widely including the brain, functional studies on FXR1 have been mostly performed in cancer cells. Limited studies have demonstrated the importance of FXR1 in the brain. In this review, we will focus on the roles of FXR1 in brain development and pathogenesis of brain disorders. We will summarize the current knowledge in FXR1 in the context of neural biology, including structural features, isoform diversity and nomenclature, expression patterns, post-translational modifications, regulatory mechanisms, and molecular functions. Overall, FXR1 emerges as an important regulator of RNA metabolism in the brain, with strong implications in neurodevelopmental and psychiatric disorders.

ARL6IP1 mediates small-molecule-induced alleviation of Alzheimer pathology through FXR1-dependent BACE1 translation initiation

Exploring the potential lead compounds for Alzheimer's disease (AD) remains one of the challenging tasks. Here, we report that the plant extract conophylline (CNP) impeded amyloidogenesis by preferentially inhibiting BACE1 translation via the 5' untranslated region (5'UTR) and rescued cognitive decline in an animal model of APP/PS1 mice. ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1) was then found to mediate the effect of CNP on BACE1 translation, amyloidogenesis, glial activation, and cognitive function. Through analysis of the 5'UTR-targetd RNA-binding proteins by RNA pulldown combined with LC-MS/MS, we found that FMR1 autosomal homolog 1 (FXR1) interacted with ARL6IP1 and mediated CNP-induced reduction of BACE1 by regulating the 5'UTR activity. Without altering the protein levels of ARL6IP1 and FXR1, CNP treatment promoted ARL6IP1 interaction with FXR1 and inhibited FXR1 binding to the 5'UTR both invitro and invivo. Collectively, CNP exhibited a therapeutic potential for AD via ARL6IP1. Through pharmacological manipulation, we uncovered a dynamic interaction between FXR1 and the 5'UTR in translational control of BACE1, adding to the understanding of the pathophysiology of AD.

FMRP, FXR1 protein and Dlg4 mRNA, which are associated with fragile X syndrome, are involved in the ubiquitin–proteasome system

The ubiquitin–proteasome system (UPS) is a proteolytic pathway that is essential for life maintenance and vital functions, and its disruption causes serious impairments, e.g., disease development. Thus, the UPS is properly regulated. Here we show novel UPS-related factors: the fragile X mental retardation 1 (FMR1) and Fmr1 autosomal homolog 1 (FXR1) proteins and discs large MAGUK scaffold protein 4 (Dlg4) mRNA, which are associated with Fragile X syndrome, are involved in UPS activity. Fmr1-, Fxr1- and Dlg4-knockdown and Fmr1- and Fxr1-knockdown resulted in increased ubiquitination and proteasome activity, respectively. FXR1 protein was further confirmed to be associated with proteasomes, and Dlg4 mRNA itself was found to be involved in the UPS. Knockdown of these genes also affected neurite outgrowth. These findings provide new insights into the regulatory mechanism of the UPS and into the interpretation of the pathogenesis of diseases in which these genes are involved as UPS-related factors.

FXR1 facilitates axitinib resistance in clear cell renal cell carcinoma via regulating KEAP1/Nrf2 signaling pathway.

Axitinib is emerging as a first-line combination treatment drug for metastatic renal cell carcinoma, but the acquired resistance significantly bothers the treatment efficacy. This article is to investigate the impact of fragile X mental retardation autosomal homolog 1 (FXR1) and its mechanistic involvement with Kelch-like epoxy chloropropan-associated protein 1 (KEAP1)/NF-E2-related factor 2 (Nrf2) pathway on cell resistance to axitinib in clear cell renal cell carcinoma (ccRCC). Establishment of axitinib resistance cells (786-O, Caki-1, 786-O/axitinib, or Caki-1/axitinib) was made, and the cells were then transfected with sh-FXR1, or co-transfected with sh-FXR1 and sh-KEAP1. The quantitative real-time PCR (qRT-PCR) and western blotting assays were employed to measure the expression of FXR1, KEAP1, Nrf2, LC3 II/I, Beclin 1, p62, MDR-1, and MRP-1. In addition, the binding between FXR1 and KEAP1 was verified by RNA-immunoprecipitation and RNA pull-down assays, and FXR1-dependent KEAP1 mRNA degradation was determined. Herein, FXR1 was demonstrated to be overexpressed in ccRCC cells, and showed higher expression in 786-O/axitinib and Caki-1/axitinib cells. Mechanistically, FXR1 enriched KEAP1 mRNA, and pulled downed by biotinylated KEAP1 probes. Results of RNA stability assay reveled that KEAP mRNA stability was suppressed by FXR1. Furthermore, knockdown of FXR1 promoted cell apoptosis and showed a restrained feature on cell resistance to axitinib. Of note, KEAP1 knockdown suppressed cell autophagy, oxidative stress, resistance to axitinib, and promoted apoptosis, despite FXR1 was downregulated in ccRCC cells. In conclusion, FXR1 played an encouraging role in ccRCC cell resistance to axitinib by modulating KEAP/Nrf2 pathway.

Teflon promotes chromosomal recruitment of homolog conjunction proteins during Drosophila male meiosis.

Meiosis in males of higher dipterans is achiasmate. In their spermatocytes, pairing of homologs into bivalent chromosomes does not include synaptonemal complex and crossover formation. While crossovers preserve homolog conjunction until anaphase I during canonical meiosis, an alternative system is used in dipteran males. Mutant screening in Drosophila melanogaster has identified teflon (tef) as being required specifically for alternative homolog conjunction (AHC) of autosomal bivalents. The additional known AHC genes, snm, uno and mnm, are needed for the conjunction of autosomal homologs and of sex chromosomes. Here, we have analyzed the pattern of TEF protein expression. TEF is present in early spermatocytes but cannot be detected on bivalents at the onset of the first meiotic division, in contrast to SNM, UNO and MNM (SUM). TEF binds to polytene chromosomes in larval salivary glands, recruits MNM by direct interaction and thereby, indirectly, also SNM and UNO. However, chromosomal SUM association is not entirely dependent on TEF, and residual autosome conjunction occurs in tef null mutant spermatocytes. The higher tef requirement for autosomal conjunction is likely linked to the quantitative difference in the amount of SUM protein that provides conjunction of autosomes and sex chromosomes, respectively. During normal meiosis, SUM proteins are far more abundant on sex chromosomes compared to autosomes. Beyond promoting SUM recruitment, TEF has a stabilizing effect on SUM proteins. Increased SUM causes excess conjunction and consequential chromosome missegregation during meiosis I after co-overexpression. Similarly, expression of SUM without TEF, and even more potently with TEF, interferes with chromosome segregation during anaphase of mitotic divisions in somatic cells, suggesting that the known AHC proteins are sufficient for establishment of ectopic chromosome conjunction. Overall, our findings suggest that TEF promotes alternative homolog conjunction during male meiosis without being part of the final physical linkage between chromosomes.

Poly C Binding Protein 2 dependent nuclear retention of the utrophin-A mRNA in C2C12 cells

ABSTRACT Upregulation of utrophin, the autosomal homologue of dystrophin, can compensate dystrophin deficiency in Duchenne Muscular Dystrophy (DMD) although the therapeutic success is yet to be achieved. The present study has identified Poly (C) binding protein 2 (PCBP2) as a post-transcriptional suppresser for the expression of utrophin-A, the muscle-specific utrophin isoform. This study confirms nuclear retention of utrophin-A mRNA in C2C12 cells, which is mediated by PCBP2. Further investigation demonstrates PCBP2-dependent nuclear retention of follistatin mRNA as well. Its involvement in nuclear retention of mRNA sheds light on a novel function of PCBP2 that makes utrophin-A mRNA less available in cytosol. PCBP2, therefore, may be a target to de-repress utrophin-A expression in DMD.

Bivalent individualization during chromosome territory formation in Drosophila spermatocytes by controlled condensin II protein activity and additional force generators.

Reduction of genome ploidy from diploid to haploid necessitates stable pairing of homologous chromosomes into bivalents before the start of the first meiotic division. Importantly, this chromosome pairing must avoid interlocking of non-homologous chromosomes. In spermatocytes of Drosophila melanogaster, where homolog pairing does not involve synaptonemal complex formation and crossovers, associations between non-homologous chromosomes are broken up by chromosome territory formation in early spermatocytes. Extensive non-homologous associations arise from the coalescence of the large blocks of pericentromeric heterochromatin into a chromocenter and from centromere clustering. Nevertheless, during territory formation, bivalents are moved apart into spatially separate subnuclear regions. The condensin II subunits, Cap-D3 and Cap-H2, have been implicated, but the remarkable separation of bivalents during interphase might require more than just condensin II. For further characterization of this process, we have applied time-lapse imaging using fluorescent markers of centromeres, telomeres and DNA satellites in pericentromeric heterochromatin. We describe the dynamics of the disruption of centromere clusters and the chromocenter in normal spermatocytes. Mutations in Cap-D3 and Cap-H2 abolish chromocenter disruption, resulting in excessive chromosome missegregation during M I. Chromocenter persistence in the mutants is not mediated by the special system, which conjoins homologs in compensation for the absence of crossovers in Drosophila spermatocytes. However, overexpression of Cap-H2 precluded conjunction between autosomal homologs, resulting in random segregation of univalents. Interestingly, Cap-D3 and Cap-H2 mutant spermatocytes displayed conspicuous stretching of the chromocenter, as well as occasional chromocenter disruption, suggesting that territory formation might involve forces unrelated to condensin II. While the molecular basis of these forces remains to be clarified, they are not destroyed by inhibitors of F actin and microtubules. Our results indicate that condensin II activity promotes chromosome territory formation in co-operation with additional force generators and that careful co-ordination with alternative homolog conjunction is crucial.

P–533 Effects of sex chromosomal complement, XX, XO, or XY, on the transcriptome and development of mouse oocytes during follicular growth

Abstract Study question How does the sex chromosome complement affect the transcriptome and development of oocytes during follicular growth in the mouse ovary? Summary answer Highly expressed X-linked genes adjust their transcript levels according to the X dosage. Y-linked genes affect the transcript levels of some X-linked and autosomal genes. What is known already Female mice carrying XO and XY chromosomes on the C57BL/6J (B6) genetic background are healthy but encounter subfertility and infertility, respectively. Our previous results have shown that the XY oocyte is defective in its cytoplasm; its replacement with that of an XX oocyte at the GV stage allows for production of healthy offspring after fertilization. Since transcription is shut down in the oocyte by the end of growth phase, the mRNAs and proteins necessary for meiotic progression and early embryonic development are accumulated during follicular growth. Study design, size, duration 30 oocytes of 50–59 μm diameter were pooled for each genotype in biological triplicate and subjected to RNA-Sequencing. Total RNA extracted from 10–30 pooled oocytes of each size range and genotype in biological triplicate were subjected to qRT-PCR. All experiments were performed between 2019–2021. Participants/materials, setting, methods XY and XO females were generated by cross between B6 females with B6.YTIR and B6.XPafY males, respectively. Oocytes in the growth phase were collected at 8–18 days postpartum (dpp), whereas fully-grown oocytes were collected at 27–29 dpp after injection with equine chorionic gonadotropin. Oocytes of 50–59 μm diameter were subjected to RNA-Sequencing using a version of SmartSeq2, followed by DEG analyses. Transcript levels in the oocytes of various diameters were determined by qRT-PCR. Main results and the role of chance Chromatin configuration, mitochondrial distribution, and de novo transcription were largely comparable among the XX, XO, and XY oocytes smaller than 60 µm. Three way comparisons of RNA-Seq data in the oocytes of 50–59 μm revealed; (1) 13.8% of X-linked DEGs showed the transcript levels in correspond to the X chromosome dosage; (2) 9 genes on the Y short arm and 2 genes near the distal end of the Y long arm were highly expressed in XY oocytes; (3) transcript levels of X- or autosomal homologs were affected by the XY complement compared to XX and XO oocytes; and (4) 54 and 39 X-linked and autosomal genes show higher and lower transcript levels, respectively, in XY oocytes compared to XX and XO oocytes. The results of qRT-PCR of selected genes revealed distinct dynamic changes in transcript levels in the oocyte during follicular growth. Data of RNA-Seq were statistically analyzed using R Bioconductor limma package for differentially expressed genes having Benjamini-Hochberg adjusted P values lower than 0.01 and log2 fold change higher than 1. All data of qRT-PCR were statistically analyzed by one-way ANOVA followed by Tukey’s honestly significant difference (HSD) test. Limitations, reasons for caution In humans, most XO females die in utero and those who reach the term suffer from congenital abnormalities and infertility (Turner’s syndrome). However, the severer phenotype can be attributed to somatic cells with a greater number of genes that escape from X chromosome inactivation in humans than mice. Wider implications of the findings: XO and XY mice provide animal models for investigating the consequence of X haplodeficiency in the female germline, independent of somatic defects. Furthermore, XY female mice provide a unique opportunity for examining whether and how Y-linked genes are transcribed outside the male germline. Trial registration number Not applicable

Loss of sarcospan exacerbates pathology in mdx mice, but does not affect utrophin amelioration of disease.

The dystrophin-glycoprotein complex (DGC) is a membrane adhesion complex that provides structural stability at the sarcolemma by linking the myocyte's internal cytoskeleton and external extracellular matrix. In Duchenne muscular dystrophy (DMD), the absence of dystrophin leads to the loss of the DGC at the sarcolemma, resulting in sarcolemmal instability and progressive muscle damage. Utrophin (UTRN), an autosomal homolog of dystrophin, is upregulated in dystrophic muscle and partially compensates for the loss of dystrophin in muscle from patients with DMD. Here, we examine the interaction between Utr and sarcospan (SSPN), a small transmembrane protein that is a core component of both UTRN-glycoprotein complex (UGC) and DGC. We show that additional loss of SSPN causes an earlier onset of disease in dystrophin-deficient mdx mice by reducing the expression of the UGC at the sarcolemma. In order to further evaluate the role of SSPN in maintaining therapeutic levels of Utr at the sarcolemma, we tested the effect of Utr transgenic overexpression in mdx mice lacking SSPN (mdx:SSPN -/-:Utr-Tg). We found that overexpression of Utr restored SSPN to the sarcolemma in mdx muscle but that the ablation of SSPN in mdx muscle reduced Utr at the membrane. Nevertheless, Utr overexpression reduced central nucleation and improved grip strength in both lines. These findings demonstrate that high levels of Utr transgenic overexpression ameliorate the mdx phenotype independently of SSPN expression but that loss of SSPN may impair Utr-based mechanisms that rely on lower levels of Utr protein.

Platypus and echidna genomes reveal mammalian biology and evolution

Egg-laying mammals (monotremes) are the only extant mammalian outgroup to therians (marsupial and eutherian animals) and provide key insights into mammalian evolution1,2. Here we generate and analyse reference genomes of the platypus (Ornithorhynchus anatinus) and echidna (Tachyglossus aculeatus), which represent the only two extant monotreme lineages. The nearly complete platypus genome assembly has anchored almost the entire genome onto chromosomes, markedly improving the genome continuity and gene annotation. Together with our echidna sequence, the genomes of the two species allow us to detect the ancestral and lineage-specific genomic changes that shape both monotreme and mammalian evolution. We provide evidence that the monotreme sex chromosome complex originated from an ancestral chromosome ring configuration. The formation of such a unique chromosome complex may have been facilitated by the unusually extensive interactions between the multi-X and multi-Y chromosomes that are shared by the autosomal homologues in humans. Further comparative genomic analyses unravel marked differences between monotremes and therians in haptoglobin genes, lactation genes and chemosensory receptor genes for smell and taste that underlie the ecological adaptation of monotremes.

Widespread Recombination Suppression Facilitates Plant Sex Chromosome Evolution.

Classical models suggest that recombination rates on sex chromosomes evolve in a stepwise manner to localize sexually antagonistic variants in the sex in which they are beneficial, thereby lowering rates of recombination between X and Y chromosomes. However, it is also possible that sex chromosome formation occurs in regions with preexisting recombination suppression. To evaluate these possibilities, we constructed linkage maps and a chromosome-scale genome assembly for the dioecious plant Rumex hastatulus. This species has a polymorphic karyotype with a young neo-sex chromosome, resulting from a Robertsonian fusion between the X chromosome and an autosome, in part of its geographic range. We identified the shared and neo-sex chromosomes using comparative genetic maps of the two cytotypes. We found that sex-linked regions of both the ancestral and the neo-sex chromosomes are embedded in large regions of low recombination. Furthermore, our comparison of the recombination landscape of the neo-sex chromosome to its autosomal homolog indicates that low recombination rates mainly preceded sex linkage. These patterns are not unique to the sex chromosomes; all chromosomes were characterized by massive regions of suppressed recombination spanning most of each chromosome. This represents an extreme case of the periphery-biased recombination seen in other systems with large chromosomes. Across all chromosomes, gene and repetitive sequence density correlated with recombination rate, with patterns of variation differing by repetitive element type. Our findings suggest that ancestrally low rates of recombination may facilitate the formation and subsequent evolution of heteromorphic sex chromosomes.

Identification of Clock Genes Related to Hypertension in Kidney From Spontaneously Hypertensive Rats.

BackgroundThere is a diurnal variation in the blood pressure fluctuation of hypertension, and blood pressure fluctuation abnormality is considered to be an independent risk factor for organ damage including cardiovascular complications. In the current study, we tried to identify molecules responsible for blood pressure circadian rhythm formation under the control of the kidney biological clock in hypertension.MethodsDNA microarray analysis was performed in kidneys from 5-week-old spontaneously hypertensive rats (SHRs)/Izm, stroke-prone SHR rats (SHRSP)/Izm, and Wistar Kyoto (WKY)/Izm rats. To detect variation, mouse tubular epithelial cells (TCMK-1) were stimulated with dexamethasone. We performed immunostaining and western blot analysis in the renal medulla of kidney from 5-week-old WKY rats and SHRs.ResultsWe extracted 1,032 genes with E-box, a binding sequence for BMAL1 and CLOCK using a Gene Set Enrichment Analysis. In a microarray analysis, we identified 12 genes increased as more than 2-fold in the kidneys of SHRs and SHRSP in comparison to WKY rats. In a periodic regression analysis, phosphoribosyl pyrophosphate amidotransferase (Ppat) and fragile X mental retardation, autosomal homolog 1 (Fxr1) showed circadian rhythm. Immunocytochemistry revealed PPAT-positivity in nuclei and cytoplasm in the tubules, and FXR1-positivity in the cytoplasm of TCMK-1. In 5-week-old WKY rat and SHR kidneys, PPAT was localized in the nucleus and cytoplasm of the proximal and distal tubules, and FXR1 was localized to the cytoplasm of the proximal and distal tubules.ConclusionsPPAT and FXR1 are pivotal molecules in the control of blood pressure circadian rhythm by the kidney in hypertension.

Fxr1 regulates sleep and synaptic homeostasis

The fragile X autosomal homolog 1 (Fxr1) is regulated by lithium and has been GWAS‐associated with schizophrenia and insomnia. Homeostatic regulation of synaptic strength is essential for the maintenance of brain functions and involves both cell‐autonomous and system‐level processes such as sleep. We examined the contribution of Fxr1 to cell‐autonomous homeostatic synaptic scaling and neuronal responses to sleep loss, using a combination of gene overexpression and Crispr/Cas9‐mediated somatic knockouts to modulate gene expression. Our findings indicate that Fxr1 is downregulated during both scaling and sleep deprivation via a glycogen synthase kinase 3 beta (GSK3β)‐dependent mechanism. In both conditions, downregulation of Fxr1 is essential for the homeostatic modulation of surface AMPA receptors and synaptic strength. Preventing the downregulation of Fxr1 during sleep deprivation results in altered EEG signatures. Furthermore, sequencing of neuronal translatomes revealed the contribution of Fxr1 to changes induced by sleep deprivation. These findings uncover a role of Fxr1 as a shared signaling hub between cell‐autonomous homeostatic plasticity and system‐level responses to sleep loss, with potential implications for neuropsychiatric illnesses and treatments.

MiR-132 Regulates PTSD-like Behaviors in Rats Following Single-Prolonged Stress Through Fragile X-Related Protein 1.

Fragile X-related protein 1 (FXR1) is a member of the fragile X family of RNA-binding proteins, which regulates a number of neurological and neuropsychiatric disorders such as fragile X syndrome, and is expected as a novel therapeutic target for some psychiatric diseases. However, it is unknown how FXR1 changes and functions in post-traumatic stress disorder (PTSD), a common mental disorder related to trauma and stressor. In this study, we characterized the expression pattern of FXR1 in the pathophysiological process of PTSD and further investigated the possible mechanism underlying these changes by finding an upstream regulator, namely miRNA-132 (miR-132). Furthermore, we verified whether miR-132 silence had an effect on the PTSD-like behaviors of single prolonged stress (SPS) rats through open field test, forced swimming test, and water maze test. At last, we examined the expression levels of PSD95 and synapsin I in the hippocampus, which was one of the key brain regions associated with PTSD. We showed that the levels of FXR1 and fragile X mental retardation protein (FMRP), an autosomal homolog of FXR1, were decreased in the hippocampus of PTSD rats, but the levels of PSD95 and synapsin I were increased, which could be reversed by downregulation of miR-132. The results revealed that miR-132 could modulate PTSD-like behaviors in rats following SPS through regulating FXR1 and FMRP.

Dosage regulation, and variation in gene expression and copy number ofhuman Y chromosome ampliconic genes.

The Y chromosome harbors nine multi-copy ampliconic gene families expressed exclusively in testis. The gene copies within each family are >99% identical to each other, which poses a major challenge in evaluating their copy number. Recent studies demonstrated high variation in Y ampliconic gene copy number among humans. However, how this variation affects expression levels in human testis remains understudied. Here we developed a novel computational tool Ampliconic Copy Number Estimator (AmpliCoNE) that utilizes read sequencing depth information to estimate Y ampliconic gene copy number per family. We applied this tool to whole-genome sequencing data of 149 men with matched testis expression data whose samples are part of the Genotype-Tissue Expression (GTEx) project. We found that the Y ampliconic gene families with low copy number in humans were deleted or pseudogenized in non-human great apes, suggesting relaxation of functional constraints. Among the Y ampliconic gene families, higher copy number leads to higher expression. Within the Y ampliconic gene families, copy number does not influence gene expression, rather a high tolerance for variation in gene expression was observed in testis of presumably healthy men. No differences in gene expression levels were found among major Y haplogroups. Age positively correlated with expression levels of the HSFY and PRY gene families in the African subhaplogroup E1b, but not in the European subhaplogroups R1b and I1. We also found that expression of five Y ampliconic gene families is coordinated with that of their non-Y (i.e. X or autosomal) homologs. Indeed, five ampliconic gene families had consistently lower expression levels when compared to their non-Y homologs suggesting dosage regulation, while the HSFY family had higher expression levels than its X homolog and thus lacked dosage regulation.

Repression-free utrophin-A 5'UTR variants.

Mutation in the dystrophin gene results Duchenne Muscular Dystrophy (DMD), an X-linked fatal neuromuscular disorder. Dystrophin deficiency can be compensated by upregulation of utrophin, an autosomal homologue of dystrophin. But the expression of utrophin in adults is restricted to myotendinous and neuromuscular junctions. Therefore utrophin upregulation throughout the muscle fiber can only be achieved if we understand regulatory mechanisms behind its expression. Utrophin-A 5′UTR mediated repression of translation was reported earlier. In this article, we present evidences of two transcript variants of utrophin-A that do not confer repression to the downstream reporter ORF in mouse myoblast C2C12 cells. These repression-free variants may be targeted for utrophin upregulation.

The RNA-binding protein FXR1 modulates prostate cancer progression by regulating FBXO4.

This paper is to characterize the expression status of Fragile X Mental Retardation, Autosomal Homolog 1 (FXR1) in prostate cancer cells and understand its mechanistic involvement in the tumor biology of prostate cancer. The relative expression of FXR1 in prostate cancer cells was determined by real-time polymerase chain reaction and Western blotting. Cell proliferation in FXR1-deficient cells was evaluated by cell counting and MTT assays. The migrative and invasive capacities were measured by transwell assay. The potential regulatory effect of FXR1 on FBXO4 was interrogated using luciferase reporter assay. The direct bind of FXR1 with FBXO4 transcripts was analyzed by RNA immunoprecipitation and RNA pull-down assay. We observed aberrant overexpression of FXR1 in prostate cancer cells at both transcript and protein levels. FXR1 deficiency was associated with inhibited cell proliferation/viability and compromised migration/invasion in prostate cancer cells. Mechanistically, FXR1 negatively regulated FBXO4 transcripts via direct association with its 3'UTR and promoted mRNA degradation. FBXO4 knockdown predominantly rescued the tumor-suppressive phenotype in FXR1-deficient cells. We uncovered the oncogenic role of FXR1 in prostate cancer cells and further demonstrated its dependence on FBXO4. Our data highlight the importance of FXR1-FBXO4 signaling in prostate cancer.

Are FXR Family Proteins Integrators of Dopamine Signaling and Glutamatergic Neurotransmission in Mental Illnesses?

Dopamine receptors and related signaling pathways have long been implicated in pathophysiology and treatment of mental illnesses, including schizophrenia and bipolar disorder. Dopamine signaling may impact neuronal activity by modulation of glutamate neurotransmission. Recent evidence indicates a direct and/or indirect involvement of fragile X-related family proteins (FXR) in the regulation and mediation of dopamine receptor functions. FXRs consists of fragile X mental retardation protein 1 (Fmr1/FMRP) and its autosomal homologs Fxr1 and Fxr2. These RNA-binding proteins are enriched in the brain. Loss of function mutation in human FMR1 is the major genetic contributor to Fragile X mental retardation syndrome. Therefore, the role of FXR proteins has mostly been studied in the context of autism spectrum disorders. However, recent genome-wide association studies have linked this family to schizophrenia, bipolar disorders, and mood regulation pointing toward a broader involvement in mental illnesses. FXR family proteins play an important role in the regulation of glutamate-mediated neuronal activity and plasticity. Here, we discuss the brain-specific functions of FXR family proteins by focusing on the regulation of dopamine receptor functions, ionotropic glutamate receptors-mediated synaptic plasticity and contribution to mental illnesses. Based on recent evidence, we propose that FXR proteins are potential integrators of dopamine signaling and ionotropic glutamate transmission.

Identification of six serum antigens and autoantibodies for the detection of early stage epithelial ovarian carcinoma by bioinformatics analysis and liquid chip analysis.

The early detection of ovarian cancer is critical for improving the prognosis of patients, but there are currently insufficient tumor biomarkers for early detection owing to their low diagnostic sensitivity and specificity. The aim of the present study was to investigate the use of the serum antigens C-C motif chemokine ligand 18 and C-X-C motif chemokine ligand 1, and autoantibodies C1D, transmembrane 4 L six family member 1, zinc finger protein 675 and fragile X mental retardation 1 autosomal homolog 1, for the early screening of epithelial ovarian cancer (EOC). The expression of these sex genes/proteins in ovarian cancer and normal ovarian tissue was examined, and the potential functions of the six genes/proteins in ovarian cancer were analyzed by bioinformatics. Finally, these data were verified in clinical samples, and the multi-analyte suspension array method was compared with the ELISA method. Taken together, these data indicated that these six genes/proteins may serve as potential biomarkers for the early detection of EOC.

Increased Cardiac Arrhythmogenesis Associated With Gap Junction Remodeling With Upregulation of RNA-Binding Protein FXR1.

Gap junction remodeling is well established as a consistent feature of human heart disease involving spontaneous ventricular arrhythmia. The mechanisms responsible for gap junction remodeling that include alterations in the distribution of, and protein expression within, gap junctions are still debated. Studies reveal that multiple transcriptional and posttranscriptional regulatory pathways are triggered in response to cardiac disease, such as those involving RNA-binding proteins. The expression levels of FXR1 (fragile X mental retardation autosomal homolog 1), an RNA-binding protein, are critical to maintain proper cardiac muscle function; however, the connection between FXR1 and disease is not clear. To identify the mechanisms regulating gap junction remodeling in cardiac disease, we sought to identify the functional properties of FXR1 expression, direct targets of FXR1 in human left ventricle dilated cardiomyopathy (DCM) biopsy samples and mouse models of DCM through BioID proximity assay and RNA immunoprecipitation, how FXR1 regulates its targets through RNA stability and luciferase assays, and functional consequences of altering the levels of this important RNA-binding protein through the analysis of cardiac-specific FXR1 knockout mice and mice injected with 3xMyc-FXR1 adeno-associated virus. FXR1 expression is significantly increased in tissue samples from human and mouse models of DCM via Western blot analysis. FXR1 associates with intercalated discs, and integral gap junction proteins Cx43 (connexin 43), Cx45 (connexin 45), and ZO-1 (zonula occludens-1) were identified as novel mRNA targets of FXR1 by using a BioID proximity assay and RNA immunoprecipitation. Our findings show that FXR1 is a multifunctional protein involved in translational regulation and stabilization of its mRNA targets in heart muscle. In addition, introduction of 3xMyc-FXR1 via adeno-associated virus into mice leads to the redistribution of gap junctions and promotes ventricular tachycardia, showing the functional significance of FXR1 upregulation observed in DCM. In DCM, increased FXR1 expression appears to play an important role in disease progression by regulating gap junction remodeling. Together this study provides a novel function of FXR1, namely, that it directly regulates major gap junction components, contributing to proper cell-cell communication in the heart.