scholarly journals Emerging roles of the MAGE protein family in stress response pathways

2020 ◽  
Vol 295 (47) ◽  
pp. 16121-16155
Author(s):  
Rebecca R. Florke Gee ◽  
Helen Chen ◽  
Anna K. Lee ◽  
Christina A. Daly ◽  
Benjamin A. Wilander ◽  
...  
Keyword(s):  
Germ Cells ◽  
Neurodevelopmental Disorders ◽  
Molecular Level ◽  
Single Gene ◽  
Developmental Pathways ◽  
Stress Adaptation ◽  
Comprehensive Review ◽  
Melanoma Antigen ◽  
Restricted Expression Pattern ◽  
Initial Research

The melanoma antigen (MAGE) proteins all contain a MAGE homology domain. MAGE genes are conserved in all eukaryotes and have expanded from a single gene in lower eukaryotes to ∼40 genes in humans and mice. Whereas some MAGEs are ubiquitously expressed in tissues, others are expressed in only germ cells with aberrant reactivation in multiple cancers. Much of the initial research on MAGEs focused on exploiting their antigenicity and restricted expression pattern to target them with cancer immunotherapy. Beyond their potential clinical application and role in tumorigenesis, recent studies have shown that MAGE proteins regulate diverse cellular and developmental pathways, implicating them in many diseases besides cancer, including lung, renal, and neurodevelopmental disorders. At the molecular level, many MAGEs bind to E3 RING ubiquitin ligases and, thus, regulate their substrate specificity, ligase activity, and subcellular localization. On a broader scale, the MAGE genes likely expanded in eutherian mammals to protect the germline from environmental stress and aid in stress adaptation, and this stress tolerance may explain why many cancers aberrantly express MAGEs. Here, we present an updated, comprehensive review on the MAGE family that highlights general characteristics, emphasizes recent comparative studies in mice, and describes the diverse functions exerted by individual MAGEs.

scholarly journals Molecular Mechanisms of Oxytocin Signaling at the Synaptic Connection

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Jan Bakos ◽  
Annamaria Srancikova ◽  
Tomas Havranek ◽  
Zuzana Bacova
Keyword(s):  
Neurodevelopmental Disorders ◽  
Molecular Mechanisms ◽  
Neuronal Excitability ◽  
Molecular Level ◽  
Short Term ◽  
Oxytocin Receptors ◽  
Potential Therapeutic Intervention ◽  
Early Alteration

Aberrant regulation of oxytocin signaling is associated with the etiology of neurodevelopmental disorders. Synaptic dysfunctions in neurodevelopmental disorders are becoming increasingly known, and their pathogenic mechanisms could be a target of potential therapeutic intervention. Therefore, it is important to pay attention to the role of oxytocin and its receptor in synapse structure, function, and neuron connectivity. An early alteration in oxytocin signaling may disturb neuronal maturation and may have short-term and long-term pathological consequences. At the molecular level, neurodevelopmental disorders include alterations in cytoskeletal rearrangement and neuritogenesis resulting in a diversity of synaptopathies. The presence of oxytocin receptors in the presynaptic and postsynaptic membranes and the direct effects of oxytocin on neuronal excitability by regulating the activity of ion channels in the cell membrane implicate that alterations in oxytocin signaling could be involved in synaptopathies. The ability of oxytocin to modulate neurogenesis, synaptic plasticity, and certain parameters of cytoskeletal arrangement is discussed in the present review.

scholarly journals Mapping candidate genes for Drosophila melanogaster resistance to the parasitoid wasp Leptopilina boulardi

2006 ◽  
Vol 88 (2) ◽  
pp. 81-91 ◽  
Author(s):  
M. HITA ◽  
E. ESPAGNE ◽  
F. LEMEUNIER ◽  
L. PASCUAL ◽  
Y. CARTON ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Candidate Genes ◽  
Resistance Gene ◽  
Molecular Level ◽  
Single Gene ◽  
Parasitoid Wasp ◽  
Male Recombination ◽  
Leptopilina Boulardi

Drosophila melanogaster resistance against the parasitoid wasp Leptopilina boulardi is under the control of a single gene (Rlb), with two alleles, the resistant one being dominant. Using strains bearing deletions, we previously demonstrated that the 55E2–E6; 55F3 region on chromosome 2R is involved in the resistance phenomenon. In this paper, we first restricted the Rlb containing region by mapping at the molecular level the breakpoints of the Df(2R)Pc66, Df(2R)P34 and Df(2R)Pc4 deficiencies, using both chromosomal in situ hybridization and Southern analyses. The resistance gene was localized in a 100 kb fragment, predicted to contain about 10 different genes. Male recombination genetic experiments were then performed, leading to identification of two possible candidates for the Rlb gene. Potential involvement of one of this genes, edl/mae, is discussed.

scholarly journals Virulence Effectors of Pathogenic Mycoplasmas

2018 ◽  
Author(s):  
Meghan A. May ◽  
Daniel R. Brown
Keyword(s):  
Molecular Level ◽  
Mechanisms Of Action ◽  
Host Responses ◽  
Direct Effects ◽  
Biological Characterization ◽  
Comprehensive Review ◽  
Genomic Analyses ◽  
Virulence Effectors ◽  
Cards Toxin

Members of the genus Mycoplasma and related organisms impose a substantial burden of infectious diseases on humans and animals, but the last comprehensive review of mycoplasmal pathogenicity was published 20 years ago. Post-genomic analyses have now begun to support the discovery and detailed molecular biological characterization of a number of specific mycoplasmal virulence factors. This review covers three categories of defined mycoplasmal virulence effectors: 1) specific macromolecules including the superantigen MAM, the ADP-ribosylating CARDS toxin, sialidase, cytotoxic nucleases, cell-activating diacylated lipopeptides, and phosphocholine-containing glycoglycerolipids; 2) the small molecule effectors hydrogen peroxide, hydrogen sulfide, and ammonia; and 3) several putative mycoplasmal orthologs of virulence effectors documented in other bacteria.  Understanding such effectors and their mechanisms of action at the molecular level connects the biology of the bacteria to direct effects on the host and host responses they elicit, and is expected to translate into new interventions for human and veterinary mycoplasmosis.

scholarly journals Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

2020 ◽  
Author(s):  
J. den Hoed ◽  
E. de Boer ◽  
N. Voisin ◽  
A.J.M. Dingemans ◽  
N. Guex ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Transcriptional Repression ◽  
Large Scale ◽  
Phenotypic Variability ◽  
Single Gene ◽  
Independent Evidence ◽  
Mild Phenotype ◽  
Nonsense Mediated Decay ◽  
Pathophysiological Mechanisms ◽  
Binding Domains

AbstractWhereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. Contrastingly, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay and encode truncated proteins, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

Molecular characterization and phylogenetic analysis of ascarid nematodes from twenty-one species of captive wild mammals based on mitochondrial and nuclear sequences

Parasitology ◽  
2012 ◽  
Vol 139 (10) ◽  
pp. 1329-1338 ◽  
Author(s):  
YAN LI ◽  
LILI NIU ◽  
QIANG WANG ◽  
ZHIHE ZHANG ◽  
ZHIGANG CHEN ◽  
...  
Keyword(s):  
Phylogenetic Analysis ◽  
Phylogenetic Relationships ◽  
Molecular Level ◽  
Single Gene ◽  
Health Concern ◽  
Bootstrap Support ◽  
Wild Animals ◽  
Public Health Concern ◽  
Wild Mammals ◽  
High Bootstrap

SUMMARYAlthough ascarid nematodes are important parasites of wild animals of public health concern, few species of ascarids from wild animals have been studied at the molecular level so far. Here, the classification and phylogenetic relationships of roundworms from 21 species of captive wild animals have been studied by sequencing and analysis of parts of the ribosomal 18S and 28S genes and the mitochondrial (mt) 12S gene. Phylogenetic relationships were inferred by 3 methods (NJ/MP/ML) based on the data of single gene sequences and concatenated sequences. Homology analysis indicated that the 18S sequences were conserved among roundworms from all 21 species and that 28S showed interspecies variability. Divergence levels displayed in 12S suggested that 12S appears to be either intra- or interspecifically variable. Evolutionary trees indicated that the ascarids split into 2 families, 4 genera and 7 species, with high bootstrap support for each clade. Combined trees suggested that Baylisascaris ailuri is more closely related to B. transfuga than to B. schroederi. This study provides useful molecular markers for the classification, phylogenetic analysis and epidemiological investigation of roundworms from wild animals.

scholarly journals mTOR Driven Gene Transcription Is Required for Cholesterol Production in Neurons of the Developing Cerebral Cortex

2021 ◽  
Vol 22 (11) ◽  
pp. 6034
Author(s):  
Martin Schüle ◽  
Tamer Butto ◽  
Sri Dewi ◽  
Laura Schlichtholz ◽  
Susanne Strand ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Neurodevelopmental Disorders ◽  
Cholesterol Biosynthesis ◽  
Single Gene ◽  
Autism Spectrum ◽  
Altered Expression ◽  
Mtorc1 Signaling ◽  
Mtor Activity

Dysregulated mammalian target of rapamycin (mTOR) activity is associated with various neurodevelopmental disorders ranging from idiopathic autism spectrum disorders (ASD) to syndromes caused by single gene defects. This suggests that maintaining mTOR activity levels in a physiological range is essential for brain development and functioning. Upon activation, mTOR regulates a variety of cellular processes such as cell growth, autophagy, and metabolism. On a molecular level, however, the consequences of mTOR activation in the brain are not well understood. Low levels of cholesterol are associated with a wide variety of neurodevelopmental disorders. We here describe numerous genes of the sterol/cholesterol biosynthesis pathway to be transcriptionally regulated by mTOR complex 1 (mTORC1) signaling in vitro in primary neurons and in vivo in the developing cerebral cortex of the mouse. We find that these genes are shared targets of the transcription factors SREBP, SP1, and NF-Y. Prenatal as well as postnatal mTORC1 inhibition downregulated expression of these genes which directly translated into reduced cholesterol levels, pointing towards a substantial metabolic function of the mTORC1 signaling cascade. Altogether, our results indicate that mTORC1 is an essential transcriptional regulator of the expression of sterol/cholesterol biosynthesis genes in the developing brain. Altered expression of these genes may be an important factor contributing to the pathogenesis of neurodevelopmental disorders associated with dysregulated mTOR signaling.

The behavioral neurogenetics of fragile X syndrome: Analyzing gene–brain–behavior relationships in child developmental psychopathologies

2003 ◽  
Vol 15 (4) ◽  
pp. 927-968 ◽  
Author(s):  
ALLAN L. REISS ◽  
CHRISTOPHER C. DANT
Keyword(s):  
Environmental Factors ◽  
Fragile X Syndrome ◽  
Neurodevelopmental Disorders ◽  
Fragile X ◽  
Single Gene ◽  
Structure And Function ◽  
Research Approach ◽  
And Function ◽  
And Behavior ◽  
Brain Behavior

Analyzing gene–brain–behavior linkages in childhood neurodevelopmental disorders, a research approach called “behavioral neurogenetics,” has provided new insights into understanding how both genetic and environmental factors contribute to complex variations in typical and atypical human development. Research into etiologically more homogeneous disorders, such as fragile X syndrome, in particular, allows the use of more precise metrics of genetic risk so that we can more fully understand the complex pathophysiology of childhood onset neurodevelopmental disorders. In this paper, we review our laboratory's behavioral neurogenetics research by examining gene–brain–behavior relationships in fragile X syndrome, a single-gene disorder that has become a well-characterized model for studying neurodevelopmental dysfunction in childhood. Specifically, we examine genetic influences, trajectories of cognition and behavior, variation in brain structure and function, and biological and environmental factors that influence developmental and cognitive outcomes of children with fragile X. The converging approaches across these multilevel scientific domains indicate that fragile X, which arises from disruption of a single gene leading to the loss of a specific protein, is associated with a cascade of aberrations in neurodevelopment, resulting in a central nervous system that is suboptimal with respect to structure and function. In turn, structural and functional brain alterations lead to early disruption in emotion, cognition, and behavior in the child with fragile X. The combination of molecular genetics, neuroimaging, and behavioral research have advanced our understanding of the linkages between genetic variables, neurobiological measures, IQ, and behavior. Our research and that of others demonstrates that neurobehavior and neurocognition, genetics, and neuroanatomy are all different views of the same intriguing biological puzzle, a puzzle that today is rapidly emerging into a more complete picture of the intricate linkages among gene, brain, and behavior in developing children. Understanding the complex multilevel scientific perspective involved in fragile X will also contribute to our understanding of normal development by highlighting developmental events throughout the life span, thereby helping us to delineate the boundaries of pathology.

scholarly journals Tourette syndrome and other neurodevelopmental disorders: a comprehensive review

2017 ◽  
Vol 11 (1) ◽  
Author(s):  
Elena Cravedi ◽  
Emmanuelle Deniau ◽  
Marianna Giannitelli ◽  
Jean Xavier ◽  
Andreas Hartmann ◽  
...  
Keyword(s):  
Tourette Syndrome ◽  
Neurodevelopmental Disorders ◽  
Comprehensive Review
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