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Frontiers in Oncology 2022COVID-19 infection caused by SARS-CoV-2 is considered catastrophic because it affects multiple organs, particularly those of the respiratory tract. Although the... (Review)
Review
COVID-19 infection caused by SARS-CoV-2 is considered catastrophic because it affects multiple organs, particularly those of the respiratory tract. Although the consequences of this infection are not fully clear, it causes damage to the lungs, the cardiovascular and nervous systems, and other organs, subsequently inducing organ failure. In particular, the effects of SARS-CoV-2-induced inflammation on cancer cells and the tumor microenvironment need to be investigated. COVID-19 may alter the tumor microenvironment, promoting cancer cell proliferation and dormant cancer cell (DCC) reawakening. DCCs reawakened upon infection with SARS-CoV-2 can populate the premetastatic niche in the lungs and other organs, leading to tumor dissemination. DCC reawakening and consequent neutrophil and monocyte/macrophage activation with an uncontrolled cascade of pro-inflammatory cytokines are the most severe clinical effects of COVID-19. Moreover, neutrophil extracellular traps have been demonstrated to activate the dissemination of premetastatic cells into the lungs. Further studies are warranted to better define the roles of COVID-19 in inflammation as well as in tumor development and tumor cell metastasis; the results of these studies will aid in the development of further targeted therapies, both for cancer prevention and the treatment of patients with COVID-19.
PubMed: 36300087
DOI: 10.3389/fonc.2022.1029830 -
Human Mutation Jan 2018The deleted in colorectal cancer (DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline... (Review)
Review
The deleted in colorectal cancer (DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus-specific LOVD (https://databases.lovd.nl/shared/genes/DCC).
Topics: Abnormalities, Multiple; Agenesis of Corpus Callosum; Amino Acid Sequence; Binding Sites; Conserved Sequence; Databases, Genetic; Genes, DCC; Genetic Association Studies; Humans; Magnetic Resonance Imaging; Models, Molecular; Mutation; Netrin-1; Phenotype; Protein Binding; Protein Conformation; Protein Domains; Syndrome
PubMed: 29068161
DOI: 10.1002/humu.23361 -
Scientific Reports Feb 2017During development, midline crossing by axons brings into play highly conserved families of receptors and ligands. The interaction between the secreted ligand Netrin-1...
During development, midline crossing by axons brings into play highly conserved families of receptors and ligands. The interaction between the secreted ligand Netrin-1 and its receptor Deleted in Colorectal Carcinoma (DCC) is thought to control midline attraction of crossing axons. Here, we studied the evolution of this ligand/receptor couple in birds taking advantage of a wealth of newly sequenced genomes. From phylogeny and synteny analyses we can infer that the DCC gene has been conserved in most extant bird species, while two independent events have led to its loss in two avian groups, passeriformes and galliformes. These convergent accidental gene loss events are likely related to chromosome Z rearrangement. We show, using whole-mount immunostaining and 3Disco clearing, that in the nervous system of all birds that have a DCC gene, DCC protein expression pattern is similar to other vertebrates. Surprisingly, we show that the early developmental pattern of commissural tracts is comparable in all birds, whether or not they have a DCC receptor. Interestingly, only 4 of the 5 genes encoding secreted netrins, the DCC ligands in vertebrates, were found in birds, but Netrin-5 was absent. Together, these results support a remarkable plasticity of commissural axon guidance mechanisms in birds.
Topics: Animals; Avian Proteins; Axon Guidance; Axons; Biological Evolution; Birds; Brain; Conserved Sequence; DCC Receptor; Netrin-1; Neuronal Plasticity; Neurons; Phylogeny; Sequence Deletion; Vertebrates
PubMed: 28240285
DOI: 10.1038/srep37569 -
Database : the Journal of Biological... 2015The Encyclopedia of DNA elements (ENCODE) project is an ongoing collaborative effort to create a catalog of genomic annotations. To date, the project has generated over... (Review)
Review
The Encyclopedia of DNA elements (ENCODE) project is an ongoing collaborative effort to create a catalog of genomic annotations. To date, the project has generated over 4000 experiments across more than 350 cell lines and tissues using a wide array of experimental techniques to study the chromatin structure, regulatory network and transcriptional landscape of the Homo sapiens and Mus musculus genomes. All ENCODE experimental data, metadata and associated computational analyses are submitted to the ENCODE Data Coordination Center (DCC) for validation, tracking, storage and distribution to community resources and the scientific community. As the volume of data increases, the organization of experimental details becomes increasingly complicated and demands careful curation to identify related experiments. Here, we describe the ENCODE DCC's use of ontologies to standardize experimental metadata. We discuss how ontologies, when used to annotate metadata, provide improved searching capabilities and facilitate the ability to find connections within a set of experiments. Additionally, we provide examples of how ontologies are used to annotate ENCODE metadata and how the annotations can be identified via ontology-driven searches at the ENCODE portal. As genomic datasets grow larger and more interconnected, standardization of metadata becomes increasingly vital to allow for exploration and comparison of data between different scientific projects.
Topics: Animals; Data Curation; Databases, Genetic; Gene Ontology; Gene Regulatory Networks; Humans; Mice; Molecular Sequence Annotation; Transcription, Genetic
PubMed: 25776021
DOI: 10.1093/database/bav010 -
Science Advances May 2023Mirror movements (MM) disorder is characterized by involuntary movements on one side of the body that mirror intentional movements on the opposite side. We performed...
Mirror movements (MM) disorder is characterized by involuntary movements on one side of the body that mirror intentional movements on the opposite side. We performed genetic characterization of a family with autosomal dominant MM and identified , a RhoGEF, as a candidate MM gene. We found that Arhgef7 and its partner Git1 bind directly to Dcc. Dcc is the receptor for Netrin-1, an axon guidance cue that attracts commissural axons to the midline, promoting the midline crossing of axon tracts. We show that Arhgef7 and Git1 are required for Netrin-1-mediated axon guidance and act as a multifunctional effector complex. Arhgef7/Git1 activates Rac1 and Cdc42 and inhibits Arf1 downstream of Netrin-1. Furthermore, Arhgef7/Git1, via Arf1, mediates the Netrin-1-induced increase in cell surface Dcc. Mice heterozygous for have defects in commissural axon trajectories and increased symmetrical paw placements during skilled walking, a MM-like phenotype. Thus, we have delineated how mutation causes MM.
Topics: Mice; Animals; DCC Receptor; Tumor Suppressor Proteins; Nerve Growth Factors; Netrin-1; Receptors, Cell Surface; Axons
PubMed: 37172092
DOI: 10.1126/sciadv.add5501 -
Current Drug Targets Jul 2009In recent years, a number of axon guidance genes, including Netrin (Net) and Deleted in Colorectal Cancer (DCC), have been implicated in human cancers. Many of the... (Review)
Review
In recent years, a number of axon guidance genes, including Netrin (Net) and Deleted in Colorectal Cancer (DCC), have been implicated in human cancers. Many of the hallmarks of human cancer, such as cell growth, invasion, evasion of apoptosis, and formation of a blood supply to the tumor, involve cellular processes that are critical during nervous system development. Here, the roles of Net-DCC in the regulation of these cellular processes in tumors and developing neurons are discussed. The advantages of using Drosophila to study the function of Net-DCC and other axon guidance molecules in these cellular processes, as well as the potential for cancer therapeutics targeting Net-DCC are highlighted.
Topics: Animals; Apoptosis; Axons; Drosophila; Genes, DCC; Humans; Models, Animal; Neoplasms; Neovascularization, Pathologic; Netrin Receptors; Neurons; Receptors, Cell Surface
PubMed: 19601764
DOI: 10.2174/138945009788680428 -
WormBook : the Online Review of C.... Jun 2005In mammals, flies, and worms, sex is determined by distinctive regulatory mechanisms that cause males (XO or XY) and females (XX) to differ in their dose of X... (Review)
Review
In mammals, flies, and worms, sex is determined by distinctive regulatory mechanisms that cause males (XO or XY) and females (XX) to differ in their dose of X chromosomes. In each species, an essential X chromosome-wide process called dosage compensation ensures that somatic cells of either sex express equal levels of X-linked gene products. The strategies used to achieve dosage compensation are diverse, but in all cases, specialized complexes are targeted specifically to the X chromosome(s) of only one sex to regulate transcript levels. In C. elegans, this sex-specific targeting of the dosage compensation complex (DCC) is controlled by the same developmental signal that establishes sex, the ratio of X chromosomes to sets of autosomes (X:A signal). Molecular components of this chromosome counting process have been defined. Following a common step of regulation, sex determination and dosage compensation are controlled by distinct genetic pathways. C. elegans dosage compensation is implemented by a protein complex that binds both X chromosomes of hermaphrodites to reduce transcript levels by one-half. The dosage compensation complex resembles the conserved 13S condensin complex required for both mitotic and meiotic chromosome resolution and condensation, implying the recruitment of ancient proteins to the new task of regulating gene expression. Within each C. elegans somatic cell, one of the DCC components also participates in the separate mitotic/meiotic condensin complex. Other DCC components play pivotal roles in regulating the number and distribution of crossovers during meiosis. The strategy by which C. elegans X chromosomes attract the condensin-like DCC is known. Small, well-dispersed X-recognition elements act as entry sites to recruit the dosage compensation complex and to nucleate spreading of the complex to X regions that lack recruitment sites. In this manner, a repressed chromatin state is spread in cis over short or long distances, thus establishing the global, epigenetic regulation of X chromosomes that is maintained throughout the lifetime of hermaphrodites.
Topics: Animals; Caenorhabditis elegans; Chromosome Segregation; Disorders of Sex Development; Dosage Compensation, Genetic; Female; Gene Expression Regulation; Male; Sex Determination Processes; Signal Transduction; X Chromosome
PubMed: 18050416
DOI: 10.1895/wormbook.1.8.1 -
Trends in Genetics : TIG Jan 2018Recent work demonstrating the role of chromosome organization in transcriptional regulation has sparked substantial interest in the molecular mechanisms that control... (Review)
Review
Recent work demonstrating the role of chromosome organization in transcriptional regulation has sparked substantial interest in the molecular mechanisms that control chromosome structure. Condensin, an evolutionarily conserved multisubunit protein complex, is essential for chromosome condensation during cell division and functions in regulating gene expression during interphase. In Caenorhabditis elegans, a specialized condensin forms the core of the dosage compensation complex (DCC), which specifically binds to and represses transcription from the hermaphrodite X chromosomes. DCC serves as a clear paradigm for addressing how condensins target large chromosomal domains and how they function to regulate chromosome structure and transcription. Here, we discuss recent research on C. elegans DCC in the context of canonical condensin mechanisms as have been studied in various organisms.
Topics: Adenosine Triphosphatases; Animals; Caenorhabditis elegans; DNA-Binding Proteins; Dosage Compensation, Genetic; Female; Gene Expression Regulation; Multiprotein Complexes; X Chromosome
PubMed: 29037439
DOI: 10.1016/j.tig.2017.09.010 -
ELife Apr 2021The forebrain hemispheres are predominantly separated during embryogenesis by the interhemispheric fissure (IHF). Radial astroglia remodel the IHF to form a continuous...
The forebrain hemispheres are predominantly separated during embryogenesis by the interhemispheric fissure (IHF). Radial astroglia remodel the IHF to form a continuous substrate between the hemispheres for midline crossing of the corpus callosum (CC) and hippocampal commissure (HC). Deleted in colorectal carcinoma (DCC) and netrin 1 (NTN1) are molecules that have an evolutionarily conserved function in commissural axon guidance. The CC and HC are absent in and knockout mice, while other commissures are only partially affected, suggesting an additional aetiology in forebrain commissure formation. Here, we find that these molecules play a critical role in regulating astroglial development and IHF remodelling during CC and HC formation. Human subjects with mutations display disrupted IHF remodelling associated with CC and HC malformations. Thus, axon guidance molecules such as DCC and NTN1 first regulate the formation of a midline substrate for dorsal commissures prior to their role in regulating axonal growth and guidance across it.
Topics: Agenesis of Corpus Callosum; Animals; Astrocytes; COS Cells; Cell Line, Tumor; Cell Movement; Cell Shape; Chlorocebus aethiops; Corpus Callosum; DCC Receptor; Gene Expression Regulation, Developmental; Genotype; Gestational Age; HEK293 Cells; Humans; Mice, Inbred C57BL; Mice, Knockout; Morphogenesis; Mutation; Netrin-1; Phenotype; Signal Transduction; Telencephalon; Mice
PubMed: 33871356
DOI: 10.7554/eLife.61769 -
The Journal of Neuroscience : the... May 2018The axon guidance cue receptor DCC (deleted in colorectal cancer) plays a critical role in the organization of mesocorticolimbic pathways in rodents. To investigate...
The axon guidance cue receptor DCC (deleted in colorectal cancer) plays a critical role in the organization of mesocorticolimbic pathways in rodents. To investigate whether this occurs in humans, we measured (1) anatomical connectivity between the substantia nigra/ventral tegmental area (SN/VTA) and forebrain targets, (2) striatal and cortical volumes, and (3) putatively associated traits and behaviors. To assess translatability, morphometric data were also collected in -haploinsufficient mice. The human volunteers were 20 mutation carriers, 16 relatives, and 20 unrelated healthy volunteers (UHVs; 28 females). The mice were 11 and 16 wild-type C57BL/6J animals assessed during adolescence and adulthood. Compared with both control groups, the human carriers exhibited the following: (1) reduced anatomical connectivity from the SN/VTA to the ventral striatum [: = 0.0005, () = 0.60; UHV: = 0.0029, = 0.48] and ventral medial prefrontal cortex (: = 0.0031, = 0.53; UHV: = 0.034, = 0.35); (2) lower novelty-seeking scores (: = 0.034, = 0.82; UHV: = 0.019, = 0.84); and (3) reduced striatal volume (: = 0.0009, = 1.37; UHV: = 0.0054, = 0.93). Striatal volumetric reductions were also present in mice, and these were seen during adolescence ( = 0.0058, = 1.09) and adulthood ( = 0.003, = 1.26). Together these findings provide the first evidence in humans that an axon guidance gene is involved in the formation of mesocorticolimbic circuitry and related behavioral traits, providing mechanisms through which mutations might affect susceptibility to diverse neuropsychiatric disorders. Opportunities to study the effects of axon guidance molecules on human brain development have been rare. Here, the identification of a large four-generational family that carries a mutation to the axon guidance molecule receptor gene, , enabled us to demonstrate effects on mesocorticolimbic anatomical connectivity, striatal volumes, and personality traits. Reductions in striatal volumes were replicated in -haploinsufficient mice. Together, these processes might influence mesocorticolimbic function and susceptibility to diverse neuropsychiatric disorders.
Topics: Adult; Aging; Animals; Axons; DCC Receptor; Exploratory Behavior; Female; Heterozygote; Humans; Limbic System; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Neural Pathways; Personality Disorders; Prefrontal Cortex; Substance-Related Disorders; Substantia Nigra; Ventral Tegmental Area; Young Adult
PubMed: 29712788
DOI: 10.1523/JNEUROSCI.3251-17.2018