scholarly journals Connexin Expression Is Altered in Liver Development of Yotari (dab1 -/-) Mice

2021 ◽  
Vol 22 (19) ◽  
pp. 10712
Author(s):  
Vlatka Paštar ◽  
Mirela Lozić ◽  
Nela Kelam ◽  
Natalija Filipović ◽  
Branka Bernard ◽  
...  
Keyword(s):  
Drug Targets ◽  
Developmental Stages ◽  
Fluorescent Microscopy ◽  
Cell Communication ◽  
Premature Death ◽  
Liver Development ◽  
Gap Junction Intercellular Communication ◽  
Recessive Mutant ◽  
Reelin Signaling ◽  
Apoptosis Inducing Factor

Disabled-1 (Dab1) protein is an intracellular adaptor of reelin signaling required for prenatal neuronal migration, as well as postnatal neurotransmission, memory formation and synaptic plasticity. Yotari, an autosomal recessive mutant of the mouse Dab1 gene is recognizable by its premature death, unstable gait and tremor. Previous findings are mostly based on neuronal abnormalities caused by Dab1 deficiency, but the role of the reelin signaling pathway in nonneuronal tissues and organs has not been studied until recently. Hepatocytes, the most abundant cells in the liver, communicate via gap junctions (GJ) are composed of connexins. Cell communication disruption in yotari mice was examined by analyzing the expression of connexins (Cxs): Cx26, Cx32, Cx37, Cx40, Cx43 and Cx45 during liver development at 13.5 and 15.5 gestation days (E13.5 and E15.5). Analyses were performed using immunohistochemistry and fluorescent microscopy, followed by quantification of area percentage covered by positive signal. Data are expressed as a mean±SD and analyzed by one-way ANOVA. All Cxs examined displayed a significant decrease in yotari compared to wild type (wt) individuals at E13.5. Looking at E15.5 we have similar results with exception of Cx37 showing negligible expression in wt. Channels formation triggered by pathological stimuli, as well as propensity to apoptosis, was studied by measuring the expression of Pannexin1 (Panx1) and Apoptosis-inducing factor (AIF) through developmental stages mentioned above. An increase in Panx1 expression of E15.5 yotari mice, as well as a strong jump of AIF in both phases suggesting that yotari mice are more prone to apoptosis. Our results emphasize the importance of gap junction intercellular communication (GJIC) during liver development and their possible involvement in liver pathology and diagnostics where they can serve as potential biomarkers and drug targets.

scholarly journals Hypothyroidism alters mitochondrial morphology and induces release of apoptogenic proteins during rat cerebellar development

2003 ◽  
Vol 176 (3) ◽  
pp. 321-329 ◽  
Author(s):  
R Singh ◽  
G Upadhyay ◽  
MM Godbole
Keyword(s):  
Electron Microscopy ◽  
Structural Analysis ◽  
Developmental Stages ◽  
Cerebellar Development ◽  
Mitochondrial Morphology ◽  
Mitochondrial Structure ◽  
Proteolytic Cascade ◽  
Early Developmental Stages ◽  
Apoptosis Inducing Factor ◽  
Early Developmental

Thyroid hormone (TH) deficiency leads to extensive apoptosis during cerebellar development, but the mechanism still remains unclear. Different signals also converge on mitochondria during apoptosis to induce the release of apoptogenic proteins that activate proteolytic cascade through specific enzymes called caspases. Here we studied the effect of hypothyroidism on alterations in mitochondrial structure and translocation of apoptogenic molecules during rat cerebellar development. Structural analysis of mitochondria was studied by electron microscopy. The translocation of apoptogenic molecules was analyzed by Western blotting. TH deficiency led to vacuolization, enlargement and decrease in the number of cristae. The majority of the proapoptotic molecule, Bax, was localized in mitochondria under hypothyroid conditions whereas a limited presence of Bax was detected in the euthyroid state. Translocation of cytochrome c, apoptosis-inducing factor (AIF) and second mitochondrial-derived activator of caspases (SMAC) from mitochondria to cytosol was detected primarily in early developmental stages in the hypothyroid condition. These experimental results demonstrate that TH maintains mitochondrial architecture and inhibits the release of apoptogenic molecules to prevent excess apoptosis during cerebellar development.

scholarly journals Membrane architecture and adherens junctions contribute to strong Notch pathway activation

2021 ◽  
Author(s):  
Julia Falo Sanjuan ◽  
Sarah Bray
Keyword(s):  
Developmental Stages ◽  
Adherens Junctions ◽  
Notch Pathway ◽  
Cell Communication ◽  
Size Composition ◽  
Drosophila Embryo ◽  
Pathway Activation ◽  
Membrane Contacts ◽  
Specific Phase ◽  
Membrane Architecture

The Notch pathway mediates cell-to-cell communication in a variety of tissues, developmental stages and organisms. Pathway activation relies on the interaction between transmembrane ligands and receptors on adjacent cells. As such, pathway activity could be influenced by the size, composition or dynamics of contacts between membranes. The initiation of Notch signalling in the Drosophila embryo occurs during cellularization, when lateral cell membranes and adherens junctions are first being deposited, allowing us to investigate the importance of membrane architecture and specific junctional domains for signaling. By measuring Notch dependent transcription in live embryos we established that it initiates while lateral membranes are growing and that signalling onset correlates with a specific phase in their formation. However, the length of the lateral membranes per se was not limiting. Rather, the adherens junctions, which assemble concurrently with membrane deposition, contributed to the high levels of signalling required for transcription, as indicated by the consequences from depleting a-Catenin. Together, these results demonstrate that the establishment of lateral membrane contacts can be limiting for Notch trans-activation and suggest that adherens junctions play an important role in modulating Notch activity.

scholarly journals Multi-scale analysis of schizophrenia risk loci: Integrating centenarian genomes and spatio-temporal expression profiles suggests the need for adjunctive therapeutic interventions for neuropsychiatric disorders

2018 ◽  
Author(s):  
Chellappa S Anirudh ◽  
Ankit Kumar Pathak ◽  
Prashant Sinha ◽  
Ashwin K. Jainarayanan ◽  
Sanjeev Jain ◽  
...  
Keyword(s):  
Drug Targets ◽  
Developmental Stages ◽  
Expression Profiles ◽  
Disease Onset ◽  
Neuropsychiatric Disorders ◽  
Brain Regions ◽  
Therapeutic Interventions ◽  
Multiple Regions ◽  
Spatio Temporal ◽  
Approved Drugs

AbstractSchizophrenia (SZ) is a debilitating mental illness with multigenic etiology and significant heritability. Despite extensive genetic studies the molecular etiology has remained enigmatic. A recent systems biology study suggested a protein-protein interaction (PPI) network for SZ with 504 novel interactions. The onset of psychiatric disorders is predominantly during adolescence often accompanied by subtle structural abnormalities in multiple regions of the brain. The availability of BrainSpan atlas data allowed us to re-examine the genes present in SZ interactome as a function of space and time. The availability of genomes of healthy centenarians and non-psychiatric ExAC database allowed us to identify the variants of criticality. The expression of SZ candidate genes responsible for cognition and disease onset were studied in different brain regions during particular developmental stages. A subset of novel interactors detected in the network was further validated using gene-expression data of post-mortem brains of patients with psychiatric illness. We have narrowed down the list of drug targets proposed by the previous interactome study to 10 proteins. These proteins belonging to 81 biological pathways, are targeted by 34 known FDA approved drugs that have distinct potential for treatment of neuropsychiatric disorders. We also report the possibility of targeting key genes belonging to Celecoxib pharmacodynamics, Gα signaling and cGMP-PKG signaling pathways, that are non-specific to schizophrenia etiology.

scholarly journals Smooth muscle–endothelial cell communication activates Reelin signaling and regulates lymphatic vessel formation

2012 ◽  
Vol 197 (6) ◽  
pp. 837-849 ◽  
Author(s):  
Sophie Lutter ◽  
Sherry Xie ◽  
Florence Tatin ◽  
Taija Makinen
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Lymphatic Vessel ◽  
System Development ◽  
Lymphatic Vessels ◽  
Cell Communication ◽  
Nervous System Development ◽  
Proteolytic Processing ◽  
Lymphatic Capillary ◽  
Reelin Signaling

Active lymph transport relies on smooth muscle cell (SMC) contractions around collecting lymphatic vessels, yet regulation of lymphatic vessel wall assembly and lymphatic pumping are poorly understood. Here, we identify Reelin, an extracellular matrix glycoprotein previously implicated in central nervous system development, as an important regulator of lymphatic vascular development. Reelin-deficient mice showed abnormal collecting lymphatic vessels, characterized by a reduced number of SMCs, abnormal expression of lymphatic capillary marker lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), and impaired function. Furthermore, we show that SMC recruitment to lymphatic vessels stimulated release and proteolytic processing of endothelium-derived Reelin. Lymphatic endothelial cells in turn responded to Reelin by up-regulating monocyte chemotactic protein 1 (MCP1) expression, which suggests an autocrine mechanism for Reelin-mediated control of endothelial factor expression upstream of SMC recruitment. These results uncover a mechanism by which Reelin signaling is activated by communication between the two cell types of the collecting lymphatic vessels—smooth muscle and endothelial cells—and highlight a hitherto unrecognized and important function for SMCs in lymphatic vessel morphogenesis and function.

scholarly journals Proline Rich Motifs as Drug Targets in Immune Mediated Disorders

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Mythily Srinivasan ◽  
A. Keith Dunker
Keyword(s):  
Immune Response ◽  
Intermolecular Interactions ◽  
Drug Targets ◽  
Cell Communication ◽  
Helical Conformation ◽  
Side Chain ◽  
Type Ii ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Immune Mediated

The current version of the human immunome network consists of nearly 1400 interactions involving approximately 600 proteins. Intermolecular interactions mediated by proline-rich motifs (PRMs) are observed in many facets of the immune response. The proline-rich regions are known to preferentially adopt a polyproline type II helical conformation, an extended structure that facilitates transient intermolecular interactions such as signal transduction, antigen recognition, cell-cell communication and cytoskeletal organization. The propensity of both the side chain and the backbone carbonyls of the polyproline type II helix to participate in the interface interaction makes it an excellent recognition motif. An advantage of such distinct chemical features is that the interactions can be discriminatory even in the absence of high affinities. Indeed, the immune response is mediated by well-orchestrated low-affinity short-duration intermolecular interactions. The proline-rich regions are predominantly localized in the solvent-exposed regions such as the loops, intrinsically disordered regions, or between domains that constitute the intermolecular interface. Peptide mimics of the PRM have been suggested as potential antagonists of intermolecular interactions. In this paper, we discuss novel PRM-mediated interactions in the human immunome that potentially serve as attractive targets for immunomodulation and drug development for inflammatory and autoimmune pathologies.

scholarly journals Insect Stage-Specific Adenylate Cyclases Regulate Social Motility in African Trypanosomes

2014 ◽  
Vol 14 (1) ◽  
pp. 104-112 ◽  
Author(s):  
Miguel A. Lopez ◽  
Edwin A. Saada ◽  
Kent L. Hill
Keyword(s):  
Adenylate Cyclase ◽  
Drug Targets ◽  
Catalytic Domain ◽  
Cell Communication ◽  
Tsetse Fly ◽  
Microbial Pathogens ◽  
Group Level ◽  
Content Type ◽  
African Trypanosomes ◽  
Social Motility

ABSTRACTSophisticated systems for cell-cell communication enable unicellular microbes to act as multicellular entities capable of group-level behaviors that are not evident in individuals. These group behaviors influence microbe physiology, and the underlying signaling pathways are considered potential drug targets in microbial pathogens.Trypanosoma bruceiis a protozoan parasite that causes substantial human suffering and economic hardship in some of the most impoverished regions of the world.T. bruceilives on host tissue surfaces during transmission through its tsetse fly vector, and cultivation on surfaces causes the parasites to assemble into multicellular communities in which individual cells coordinate their movements in response to external signals. This behavior is termed “social motility,” based on its similarities with surface-induced social motility in bacteria, and it demonstrates that trypanosomes are capable of group-level behavior. Mechanisms governingT. bruceisocial motility are unknown. Here we report that a subset of receptor-type adenylate cyclases (ACs) in the trypanosome flagellum regulate social motility. RNA interference-mediated knockdown of adenylate cyclase 6 (AC6), or dual knockdown of AC1 and AC2, causes a hypersocial phenotype but has no discernible effect on individual cells in suspension culture. Mutation of the AC6 catalytic domain phenocopies AC6 knockdown, demonstrating that loss of adenylate cyclase activity is responsible for the phenotype. Notably, knockdown of other ACs did not affect social motility, indicating segregation of AC functions. These studies reveal interesting parallels in systems that control social behavior in trypanosomes and bacteria and provide insight into a feature of parasite biology that may be exploited for novel intervention strategies.

scholarly journals Data-driven learning how oncogenic gene expression locally alters heterocellular networks

2020 ◽  
Author(s):  
David J. Klinke ◽  
Audry Fernandez ◽  
Wentao Deng ◽  
Anika C. Pirkey
Keyword(s):  
Gene Expression ◽  
Tumor Microenvironment ◽  
Bayesian Network ◽  
Drug Targets ◽  
Network Inference ◽  
Immune Cell ◽  
Cell Communication ◽  
Pharmaceutical Drugs ◽  
Cell Level ◽  
Bayesian Network Inference

Discovering and developing pharmaceutical drugs increasingly relies on mechanistic mathematical modeling and simulation. In immuno-oncology, models that capture causal relations among genetic drivers of oncogenesis, functional plasticity, and host immunity provide an important complement to wet experiments, given the cellular complexity and dynamics within the tumor microenvironment. Unfortunately, formulating such mechanistic cell-level models currently relies on hand curation by experts, which can bias how data is interpreted or the priority of drug targets. In modeling molecular-level networks, rules and algorithms have been developed to limit a priori biases in formulating mechanistic models. To realize an equivalent approach for cell-level networks, we combined digital cytometry with Bayesian network inference to generate causal models that link an increase in gene expression associated with oncogenesis with alterations in stromal and immune cell subsets directly from bulk transcriptomic datasets. To illustrate, we predicted how an increase in expression of Cell Communication Network factor 4 (CCN4/WISP1) altered the tumor microenvironment using data from patients diagnosed with breast cancer and melanoma. Network predictions were then tested using two immunocompetent mouse models for melanoma. In contrast to hand-curated approaches, we posit that combining digital cytometry with Bayesian network inference provides a less biased approach for elaborating mechanistic cell-level models directly from data.

scholarly journals An RNA Interference Tool to Silence Genes in Sarcoptes scabiei Eggs

2022 ◽  
Vol 23 (2) ◽  
pp. 873
Author(s):  
Deepani D. Fernando ◽  
Pasi K. Korhonen ◽  
Robin B. Gasser ◽  
Katja Fischer
Keyword(s):  
Rna Interference ◽  
Drug Targets ◽  
Target Genes ◽  
Developmental Stages ◽  
Single Copy ◽  
Sarcoptes Scabiei ◽  
Rnai Pathway ◽  
Larval Hatching ◽  
Parasitic Mite ◽  
Pre Treatment

In a quest for new interventions against scabies—a highly significant skin disease of mammals, caused by a parasitic mite Sarcoptes scabiei—we are focusing on finding new intervention targets. RNA interference (RNAi) could be an efficient functional genomics approach to identify such targets. The RNAi pathway is present in S. scabiei and operational in the female adult mite, but other developmental stages have not been assessed. Identifying potential intervention targets in the egg stage is particularly important because current treatments do not kill this latter stage. Here, we established an RNAi tool to silence single-copy genes in S. scabiei eggs. Using sodium hypochlorite pre-treatment, we succeeded in rendering the eggshell permeable to dsRNA without affecting larval hatching. We optimised the treatment of eggs with gene-specific dsRNAs to three single-copy target genes (designated Ss-Cof, Ss-Ddp, and Ss-Nan) which significantly and repeatedly suppressed transcription by ~66.6%, 74.3%, and 84.1%, respectively. Although no phenotypic alterations were detected in dsRNA-treated eggs for Ss-Cof and Ss-Nan, the silencing of Ss-Ddp resulted in a 38% reduction of larval hatching. This RNAi method is expected to provide a useful tool for larger-scale functional genomic investigations for the identification of essential genes as potential drug targets.

scholarly journals Insulin signaling mediates neurodegeneration in glioma

2020 ◽  
Author(s):  
Patricia Jarabo ◽  
Carmen de Pablo ◽  
Héctor Herranz ◽  
Francisco Antonio Martín ◽  
Sergio Casas-Tintó
Keyword(s):  
Insulin Signaling ◽  
Neuronal Degeneration ◽  
Tumour Progression ◽  
Cell Communication ◽  
Premature Death ◽  
Insulin Pathway ◽  
Communication Signals ◽  
Synapse Loss ◽  
Neurodegenerative Process ◽  
Mitochondrial Disruption

AbstractCell to cell communication facilitates tissue development and physiology. Under pathological conditions, brain tumors disrupt glia-neuron communication signals that in consequence, promote tumor expansion at the expense of surrounding healthy tissue. The glioblastoma is the most aggressive and frequent brain tumor. This type of glioma expands and infiltrates into the brain, causing neuronal degeneration and neurological decay, among other symptoms. Here we describe how the glioblastoma produce ImpL2, an antagonist of the insulin pathway, which is regulated by the microRNA miR-8. ImpL2 targets neighboring neurons and causes mitochondrial disruption as well as synapse loss, both early symptoms of neurodegeneration. Furthermore, glioblastoma progression requires insulin pathway attenuation in neurons. Restoration of neuronal insulin activity is sufficient to rescue the synapse loss and to delay the premature death caused by glioma. Therefore, signals from GB to neuron emerge as a potential field of study to prevent neurodegeneration and to develop anti-tumoral strategies.Significance StatementGlioblastoma (GB) is the most aggressive type of brain tumour and currently there is no cure or effective treatment. Patients course with neurological decay and previous data in animal models indicate that GB cause a neurodegenerative process. We describe here a molecule named ImpL2 that is produced by GB cells and impact on neighbouring neurons. ImpL2 is an antagonist of the insulin pathway and signaling reduction in neurons causes mitochondrial defects and synapse loss. These mechanisms underlying GB-induced neurodegeneration plays a central role in the premature death caused by this tumour. Restoration of insulin signaling in neurons prevents tumour progression and rescues the lethality caused by GB in Drosophila models.

Developmental stages in the formation of inverted gap junctions during turnover in the adult horseshoe crab, Limulus

1978 ◽  
Vol 32 (1) ◽  
pp. 293-305
Author(s):  
N.J. Lane
Keyword(s):  
Gap Junctions ◽  
Normal Cell ◽  
Horseshoe Crab ◽  
Developmental Stages ◽  
Cell Communication ◽  
Central Channel ◽  
Cell Turnover ◽  
Linear Arrays ◽  
Freeze Fracturing ◽  
Small Clusters

Stages leading to the formation of inverted gap junctions between certain basal replacement or interstitial cells in the mid-gut of adult Limulus can be followed by freeze-fracturing. Free, 13-nm EF intramembranous particles first appear to be organized into short linear arrays or small clusters of particles, which then become transformed into anastomosing particulate networks covering a considerable surface area. These subsequently become concentrated into smaller, more nearly circular, macular plaques of EF particles or PF pits. These EF particles, both when free or assembled into macular arrays, possess a central channel or pore. Numerous formed gap junctions are present in Limulus mid-gut, which suggests that cell-to-cell communication is an important feature of the mature tissue. The results show that arthropod tissues can be used to study the development of gap junctions not only in differentiating systems but also in adult tissues during normal cell turnover.

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