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Gastroenterology Research Feb 2020Colon cancer is a common preventable cancer. With the adoption of widespread colon cancer screening in the developed countries, the incidence and mortality of colon... (Review)
Review
Colon cancer is a common preventable cancer. With the adoption of widespread colon cancer screening in the developed countries, the incidence and mortality of colon cancer have decreased in the targeted population. But unfortunately, the incidence and mortality of colorectal cancer (CRC) have been increasing over the last 25 years in the young adults below the age of 50. There is disparity in benefit, i.e. reduction in risk of death between right-sided and left-sided colon cancer by screening colonoscopy. The reason could be multifactorial and various measures have been taken to decrease this disparity. Although most of the screened populations are average risk individuals, a minority of the population have various risk factors for developing colon cancer and need to follow specific colon cancer screening guidelines. Gene mutations (adenomatous polyposis coli (APC), deleted in colon cancer (DCC), K-ras, p53, B-Raf proto-oncogene serine/threonine kinase (BRAF), mismatch repair genes) and microsatellite instability lead to the development of colon cancer. Although various non-invasive methods of colon cancer screening are now available, colonoscopy remains the gold standard of colon cancer screening and adenoma detection rate is now being used as the quality metrics in screening colonoscopy. Although Multi-Society Task Force (MSTF) and American College of Physicians (ACP) recommend initiating screening colonoscopy at age 50 years in all individuals except African Americans who should begin screening colonoscopy at age 45 years, the American Cancer Society (ACS) recommends initiating screening colonoscopy at age 45 years in all individuals irrespective of race and ethnicity. Low-volume split-dose prep has been found to be as effective as high-volume split-dose prep and more tolerable to patients with increased compliance. Boston bowel preparation scale is recommended to measure the quality of colon cleansing. CRC is curative if it is diagnosed at an early stage but various palliative treatment options (endoscopic, oncologic and surgical) are available in advanced stages of this cancer. Adequate number of lymph node assessment during surgery is essential in accurate staging of CRC. Checkpoint inhibitors have been found to have dramatic response and durable clinical benefit in dMMR/MSI-H metastatic CRC. Different genetic and immune-oncologic research trials are ongoing for early detection and better management of CRC.
PubMed: 32095167
DOI: 10.14740/gr1239 -
ELife Apr 2023Mutations in the ubiquitin (Ub) chaperone ) cause X-linked forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) through unknown mechanisms....
Mutations in the ubiquitin (Ub) chaperone ) cause X-linked forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) through unknown mechanisms. Here, we show that aggregation-prone, ALS-associated mutants of UBQLN2 (UBQLN2) trigger heat stress-dependent neurodegeneration in . A genetic modifier screen implicated endolysosomal and axon guidance genes, including the netrin receptor, Unc-5, as key modulators of UBQLN2 toxicity. Reduced gene dosage of or its coreceptor diminished neurodegenerative phenotypes, including motor dysfunction, neuromuscular junction defects, and shortened lifespan, in flies expressing UBQLN2 alleles. Induced pluripotent stem cells (iPSCs) harboring UBQLN2 knockin mutations exhibited lysosomal defects while inducible motor neurons (iMNs) expressing UBQLN2 alleles exhibited cytosolic UBQLN2 inclusions, reduced neurite complexity, and growth cone defects that were partially reversed by silencing of and . The combined findings suggest that altered growth cone dynamics are a conserved pathomechanism in UBQLN2-associated ALS/FTD.
Topics: Humans; Amyotrophic Lateral Sclerosis; Frontotemporal Dementia; Axon Guidance; Adaptor Proteins, Signal Transducing; Autophagy-Related Proteins; Mutation; Transcription Factors; Ubiquitins; Netrin Receptors
PubMed: 37039476
DOI: 10.7554/eLife.84382 -
Frontiers in Genetics 2014In many organisms sexual fate is determined by a chromosome-based method which entails a difference in sex chromosome-linked gene dosage. Consequently, a gene regulatory... (Review)
Review
In many organisms sexual fate is determined by a chromosome-based method which entails a difference in sex chromosome-linked gene dosage. Consequently, a gene regulatory mechanism called dosage compensation equalizes X-linked gene expression between the sexes. Dosage compensation initiates as cells transition from pluripotency to differentiation. In Caenorhabditis elegans, dosage compensation is achieved by the dosage compensation complex (DCC) binding to both X chromosomes in hermaphrodites to downregulate gene expression by twofold. The DCC contains a subcomplex (condensin I(DC)) similar to the evolutionarily conserved condensin complexes which play a fundamental role in chromosome dynamics during mitosis. Therefore, mechanisms related to mitotic chromosome condensation are hypothesized to mediate dosage compensation. Consistent with this hypothesis, monomethylation of histone H4 lysine 20 is increased, whereas acetylation of histone H4 lysine 16 is decreased, both on mitotic chromosomes and on interphase dosage compensated X chromosomes in worms. These observations suggest that interphase dosage compensated X chromosomes maintain some characteristics associated with condensed mitotic chromosome. This chromosome state is stably propagated from one cell generation to the next. In this review we will speculate on how the biochemical activities of condensin can achieve both mitotic chromosome compaction and gene repression.
PubMed: 25628648
DOI: 10.3389/fgene.2014.00473 -
Cell Reports May 2023Dynamic and coordinated axonal responses to changing environments are critical for establishing neural connections. As commissural axons migrate across the CNS midline,...
Dynamic and coordinated axonal responses to changing environments are critical for establishing neural connections. As commissural axons migrate across the CNS midline, they are suggested to switch from being attracted to being repelled in order to approach and to subsequently leave the midline. A molecular mechanism that is hypothesized to underlie this switch in axonal responses is the silencing of Netrin1/Deleted in Colorectal Carcinoma (DCC)-mediated attraction by the repulsive SLIT/ROBO1 signaling. Using in vivo approaches including CRISPR-Cas9-engineered mouse models of distinct Dcc splice isoforms, we show here that commissural axons maintain responsiveness to both Netrin and SLIT during midline crossing, although likely at quantitatively different levels. In addition, full-length DCC in collaboration with ROBO3 can antagonize ROBO1 repulsion in vivo. We propose that commissural axons integrate and balance the opposing DCC and Roundabout (ROBO) signaling to ensure proper guidance decisions during midline entry and exit.
Topics: Animals; Mice; Nerve Tissue Proteins; Receptors, Immunologic; Axon Guidance; Axons; Netrins; Gene Expression Regulation, Developmental; DCC Receptor
PubMed: 37149867
DOI: 10.1016/j.celrep.2023.112455 -
The EMBO Journal Feb 2021The netrin-1/DCC ligand/receptor pair has key roles in central nervous system (CNS) development, mediating axonal, and neuronal navigation. Although expression of...
The netrin-1/DCC ligand/receptor pair has key roles in central nervous system (CNS) development, mediating axonal, and neuronal navigation. Although expression of netrin-1 and DCC is maintained in the adult brain, little is known about their role in mature neurons. Notably, netrin-1 is highly expressed in the adult substantia nigra, leading us to investigate a role of the netrin-1/DCC pair in adult nigral neuron fate. Here, we show that silencing netrin-1 in the adult substantia nigra of mice induces DCC cleavage and a significant loss of dopamine neurons, resulting in motor deficits. Because loss of adult dopamine neurons and motor impairments are features of Parkinson's disease (PD), we studied the potential impact of netrin-1 in different animal models of PD. We demonstrate that both overexpression of netrin-1 and brain administration of recombinant netrin-1 are neuroprotective and neurorestorative in mouse and rat models of PD. Of interest, we observed that netrin-1 levels are significantly reduced in PD patient brain samples. These results highlight the key role of netrin-1 in adult dopamine neuron fate, and the therapeutic potential of targeting netrin-1 signaling in PD.
Topics: Animals; Cell Death; DCC Receptor; Disease Models, Animal; Dopaminergic Neurons; Down-Regulation; Female; Gene Silencing; Humans; Male; Mice; Netrin-1; Parkinson Disease; Rats; Signal Transduction; Substantia Nigra
PubMed: 33351190
DOI: 10.15252/embj.2020105537 -
International Journal of Molecular... Feb 2017Netrin-1 was the first axon guidance molecule to be discovered in vertebrates and has a strong chemotropic function for axonal guidance, cell migration, morphogenesis... (Review)
Review
Netrin-1 was the first axon guidance molecule to be discovered in vertebrates and has a strong chemotropic function for axonal guidance, cell migration, morphogenesis and angiogenesis. It is a secreted axon guidance cue that can trigger attraction by binding to its canonical receptors Deleted in Colorectal Cancer (DCC) and Neogenin or repulsion through binding the DCC/Uncoordinated (Unc5) A-D receptor complex. The crystal structures of Netrin-1/receptor complexes have recently been revealed. These studies have provided a structure based explanation of Netrin-1 bi-functionality. Netrin-1 and its receptor are continuously expressed in the adult nervous system and are differentially regulated after nerve injury. In the adult spinal cord and optic nerve, Netrin-1 has been considered as an inhibitor that contributes to axon regeneration failure after injury. In the peripheral nervous system, Netrin-1 receptors are expressed in Schwann cells, the cell bodies of sensory neurons and the axons of both motor and sensory neurons. Netrin-1 is expressed in Schwann cells and its expression is up-regulated after peripheral nerve transection injury. Recent studies indicated that Netrin-1 plays a positive role in promoting peripheral nerve regeneration, Schwann cell proliferation and migration. Targeting of the Netrin-1 signaling pathway could develop novel therapeutic strategies to promote peripheral nerve regeneration and functional recovery.
Topics: Animals; Cell Movement; Gene Expression; Humans; Nerve Growth Factors; Nerve Regeneration; Netrin-1; Optic Nerve; Peripheral Nerve Injuries; Protein Binding; Protein Interaction Domains and Motifs; Protein Multimerization; Receptors, Polymeric Immunoglobulin; Schwann Cells; Signal Transduction; Spinal Cord; Spinal Cord Injuries; Tumor Suppressor Proteins
PubMed: 28245592
DOI: 10.3390/ijms18030491 -
Molecular Psychiatry Jun 2022Inhibitory control deficits are prevalent in multiple neuropsychiatric conditions. The communication- as well as the connectivity- between corticolimbic regions of the...
Inhibitory control deficits are prevalent in multiple neuropsychiatric conditions. The communication- as well as the connectivity- between corticolimbic regions of the brain are fundamental for eliciting inhibitory control behaviors, but early markers of vulnerability to this behavioral trait are yet to be discovered. The gradual maturation of the prefrontal cortex (PFC), in particular of the mesocortical dopamine innervation, mirrors the protracted development of inhibitory control; both are present early in life, but reach full maturation by early adulthood. Evidence suggests the involvement of the Netrin-1/DCC signaling pathway and its associated gene networks in corticolimbic development. Here we investigated whether an expression-based polygenic score (ePRS) based on corticolimbic-specific DCC gene co-expression networks associates with impulsivity-related phenotypes in community samples of children. We found that lower ePRS scores associate with higher measurements of impulsive choice in 6-year-old children tested in the Information Sampling Task and with impulsive action in 6- and 10-year-old children tested in the Stop Signal Task. We also found the ePRS to be a better overall predictor of impulsivity when compared to a conventional PRS score comparable in size to the ePRS (4515 SNPs in our discovery cohort) and derived from the latest GWAS for ADHD. We propose that the corticolimbic DCC-ePRS can serve as a novel type of marker for impulsivity-related phenotypes in children. By adopting a systems biology approach based on gene co-expression networks and genotype-gene expression (rather than genotype-disease) associations, these results further validate our methodology to construct polygenic scores linked to the overall biological function of tissue-specific gene networks.
Topics: Adult; Child; DCC Receptor; Dopamine; Gene Regulatory Networks; Genes, DCC; Humans; Impulsive Behavior; Prefrontal Cortex
PubMed: 35388180
DOI: 10.1038/s41380-022-01533-7 -
Cell Feb 1991Using a sensitive assay for RNA expression, we identified several abnormally spliced transcripts in which exons from a candidate tumor suppressor gene (DCC) were...
Using a sensitive assay for RNA expression, we identified several abnormally spliced transcripts in which exons from a candidate tumor suppressor gene (DCC) were scrambled during the splicing process in vivo. Cloning and sequencing of PCR-amplified segments of the abnormally spliced transcripts showed that exons were joined accurately at consensus splice sites, but in an order different from that present in the primary transcript. Four scrambled transcripts were identified, each involving a different pair of exons. The scrambled transcripts were found at relatively low levels in a variety of normal and neoplastic cells of rodent and human origin, primarily in the nonpolyadenylated component of cytoplasmic RNA. These results demonstrate that the splicing process does not always pair sequential exons in the order predicted from their positions in genomic DNA, thus creating a novel type of RNA product.
Topics: Amino Acid Sequence; Animals; Base Sequence; Chromosomes, Human, Pair 18; Exons; Genes, Tumor Suppressor; Humans; Molecular Sequence Data; Oligonucleotides; Polymerase Chain Reaction; RNA Splicing; RNA, Messenger; Rats
PubMed: 1991322
DOI: 10.1016/0092-8674(91)90244-s -
International Journal of Implant... May 2022Periodontitis is an infectious disease, and a risk factor for peri-implantitis that could result in the implant loss. DNA methylation has an essential role in the...
BACKGROUND
Periodontitis is an infectious disease, and a risk factor for peri-implantitis that could result in the implant loss. DNA methylation has an essential role in the etiology and pathogenesis of inflammatory disease. However, there is lack of study on methylation status of genes in periodontitis. This study sought to explore the gene methylation profiling microarray in periodontitis.
METHODS
Through searching in the Gene Expression Omnibus database, a gene methylation profiling data set GSE173081 was identified, which included 12 periodontitis samples and 12 normal samples, respectively. Thereafter, the data of GSE173081 was downloaded and analyzed to determined differentially methylated genes (DMGs), which then were used to perform Gene Ontology analysis and pathway enrichment analyses through online database. In addition, the DMGs were applied to construct the protein-protein interaction (PPI) network information, predict the hub genes in pathology of periodontitis.
RESULTS
In total 668 DMGs were sorted and identified from the data set, which included 621 hypo-methylated genes and 47 hyper-methylated genes. Through the function and ontology analysis, these 668 genes are mainly classified into intracellular signaling pathway, cell components, cell-cell interaction, and cellular behaviors. The pathway analysis showed that the hypo-methylated genes were mostly enriched in the pathway of cGMP-PKG signaling pathway; RAF/MAP kinase; PI3K-Akt signaling pathway, while hyper-methylated genes were mostly enriched in the pathway of bacterial invasion of epithelial cells; sphingolipid signaling pathway and DCC mediated attractive signaling. The PPI network contained 630 nodes and 1790 interactions. Moreover, further analysis identified top 10 hub genes (APP; PAX6; LPAR1; WNT3A; BMP2; PI3KR2; GATA4; PLCB1; GATA6; CXCL12) as central nodes that are involved in the immune system and the inflammatory response.
CONCLUSIONS
This study provides comprehensive information of methylation status of genes to the revelation of periodontitis pathogenesis that may contribute to future research on periodontitis.
Topics: DNA Methylation; Gene Expression Profiling; Gene Regulatory Networks; Humans; Periodontitis; Phosphatidylinositol 3-Kinases
PubMed: 35491409
DOI: 10.1186/s40729-022-00420-8 -
Developmental Dynamics : An Official... Apr 2018Axons need to be properly guided to their targets to form synaptic connections, and this requires interactions between highly conserved extracellular and transmembrane... (Review)
Review
Axons need to be properly guided to their targets to form synaptic connections, and this requires interactions between highly conserved extracellular and transmembrane ligands and their cell surface receptors. The majority of studies on axon guidance signaling pathways have focused on the role of these pathways in rearranging the local cytoskeleton and plasma membrane in growth cones and axons. However, a smaller body of work has demonstrated that axon guidance signaling pathways also control gene expression via local translation and transcription. Recent studies on axon guidance ligands and receptors have begun to uncover the requirements for these alternative mechanisms in processes required for neural circuit formation: axon guidance, synaptogenesis, and cell migration. Understanding the mechanisms by which axon guidance signaling regulates local translation and transcription will create a more complete picture of neural circuit formation, and they may be applied more broadly to other tissues where axon guidance ligands and receptors are required for morphogenesis. Developmental Dynamics 247:571-580, 2018. © 2017 Wiley Periodicals, Inc.
Topics: Animals; Axon Guidance; Gene Expression Regulation; Humans; Ligands; Receptors, Cell Surface; Signal Transduction
PubMed: 29226467
DOI: 10.1002/dvdy.24609