scholarly journals Evolution of Endolymph Secretion and Endolymphatic Potential Generation in the Vertebrate Inner Ear

2018 ◽  
Vol 92 (1-2) ◽  
pp. 1-31 ◽  
Author(s):  
Christine Köppl ◽  
Viviane Wilms ◽  
Ian John Russell ◽  
Hans Gerd Nothwang
Keyword(s):  
Inner Ear ◽  
Lateral Line ◽  
Vestibular System ◽  
Molecular Mechanisms ◽  
Receptor Potential ◽  
Cell Types ◽  
Cell Receptor ◽  
Striking Difference ◽  
High K ◽  
Endolymphatic Potential

The ear of extant vertebrates reflects multiple independent evolutionary trajectories. Examples include the middle ear or the unique specializations of the mammalian cochlea. Another striking difference between vertebrate inner ears concerns the differences in the magnitude of the endolymphatic potential. This differs both between the vestibular and auditory part of the inner ear as well as between the auditory periphery in different vertebrates. Here we provide a comparison of the cellular and molecular mechanisms in different endorgans across vertebrates. We begin with the lateral line and vestibular systems, as they likely represent plesiomorphic conditions, then review the situation in different vertebrate auditory endorgans. All three systems harbor hair cells bathed in a high (K+) environment. Superficial lateral line neuromasts are bathed in an electrogenically maintained high (K+) microenvironment provided by the complex gelatinous cupula. This is associated with a positive endocupular potential. Whether this is a special or a universal feature of lateral line and possibly vestibular cupulae remains to be discovered. The vestibular system represents a closed system with an endolymph that is characterized by an enhanced (K+) relative to the perilymph. Yet only in land vertebrates does (K+) exceed (Na+). The endolymphatic potential ranges from +1 to +11 mV, albeit we note intriguing reports of substantially higher potentials of up to +70 mV in the cupula of ampullae of the semicircular canals. Similarly, in the auditory system, a high (K+) is observed. However, in contrast to the vestibular system, the positive endolymphatic potential varies more substantially between vertebrates, ranging from near zero mV to approximately +100 mV. The tissues generating endolymph in the inner ear show considerable differences in cell types and location. So-called dark cells and the possibly homologous ionocytes in fish appear to be the common elements, but there is always at least one additional cell type present. To inspire research in this field, we propose a classification for these cell types and discuss potential evolutionary relationships. Their molecular repertoire is largely unknown and provides further fertile ground for future investigation. Finally, we propose that the ultimate selective pressure for an increased endolymphatic potential, as observed in mammals and to a lesser extent in birds, is specifically to maintain the AC component of the hair-cell receptor potential at high frequencies. In summary, we identify intriguing questions for future directions of research into the molecular and cellular basis of the endolymph in the different compartments of the inner ear. The answers will provide important insights into evolutionary and developmental processes in a sensory organ essential to many species, including humans.

Identification of dysregulated genes in lymphocytes from children with Down syndrome

Genome ◽  
2008 ◽  
Vol 51 (1) ◽  
pp. 19-29 ◽  
Author(s):  
Cesar A. Sommer ◽  
Erika C. Pavarino-Bertelli ◽  
Eny M. Goloni-Bertollo ◽  
Flavio Henrique-Silva
Keyword(s):  
Gene Expression ◽  
Down Syndrome ◽  
Trisomy 21 ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cell Receptor ◽  
Chromosome 21 ◽  
Global Changes ◽  
Real Time Quantitative Pcr ◽  
Functional Classes

The molecular mechanisms by which trisomy of human chromosome 21 disrupts normal development are not well understood. Global transcriptome studies attempting to analyze the consequences of trisomy in Down syndrome (DS) tissues have reported conflicting results, which have led to the suggestion that the analysis of specific tissues or cell types may be more productive. In the present study, we set out to analyze global changes of gene expression in lymphocytes from children with trisomy 21 by means of the serial analysis of gene expression (SAGE) methodology. Two SAGE libraries were constructed using pooled RNA of normal and Down syndrome children. Comparison between DS and normal profiles revealed that most of the transcripts were expressed at similar levels and functional classes of abundant genes were equally represented. Among the 242 significantly differentially expressed SAGE tags, several transcripts downregulated in DS code for proteins involved in T-cell and B-cell receptor signaling (e.g., PI3Kδ, RGS2, LY6E, FOS, TAGAP, CD46). The SAGE data and interindividual variability were validated by real-time quantitative PCR. Our results indicate that trisomy 21 induces a modest dysregulation of disomic genes that may be related to the immunological perturbations seen in DS.

scholarly journals Creatine kinase in epithelium of the inner ear.

1992 ◽  
Vol 40 (2) ◽  
pp. 185-192 ◽  
Author(s):  
S S Spicer ◽  
B A Schulte
Keyword(s):  
Creatine Kinase ◽  
Inner Ear ◽  
Vestibular System ◽  
Hair Cells ◽  
Stria Vascularis ◽  
Photoreceptor Cells ◽  
Cell Types ◽  
Dark Cells ◽  
Transitional Cells ◽  
Marginal Cells

Epithelium of the inner ear in the gerbil and mouse was examined immunocytochemically for presence of creatine kinase (CK). Marginal cells of the cochlear stria vascularis and dark cells and transitional cells of the vestibular system were found to contain an abundance of the MM isozyme (MM-CK). CK in these cells concurs with that which is coupled to Na,K-ATPase in other cells and is considered to supply ATP for the Na,K-ATPase that mediates the high KCl of endolymph. Inner hair cells revealed content of the BB isozyme and in this respect resembled the energy-transducing photoreceptor cells in retina. In addition, outer phalangeal (Deiters') cells stained for both MM- and BB-CK whereas inner phalangeal cells evidenced content of only the BB isozyme. Immunolocalization of CK appeared similar in mouse and gerbil inner ear. Specificity of the staining was affirmed by observations in agreement with those reported for CK in various cell types and by staining with antisera from more than one source.

scholarly journals The thymus medulla and its control of αβT cell development

2020 ◽  
Author(s):  
Emilie J. Cosway ◽  
Kieran D. James ◽  
Beth Lucas ◽  
Graham Anderson ◽  
Andrea J. White
Keyword(s):  
T Cells ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Critical Role ◽  
Cell Types ◽  
Cell Receptor ◽  
Ongoing Research ◽  
Receptor Repertoire ◽  
Repertoire Diversity ◽  
Killer T Cells

AbstractαβT cells are an essential component of effective immune responses. The heterogeneity that lies within them includes subsets that express diverse self-MHC-restricted αβT cell receptors, which can be further subdivided into CD4+ helper, CD8+ cytotoxic, and Foxp3+ regulatory T cells. In addition, αβT cells also include invariant natural killer T cells that are very limited in αβT cell receptor repertoire diversity and recognise non-polymorphic CD1d molecules that present lipid antigens. Importantly, all αβT cell sublineages are dependent upon the thymus as a shared site of their development. Ongoing research has examined how the thymus balances the intrathymic production of multiple αβT cell subsets to ensure correct formation and functioning of the peripheral immune system. Experiments in both wild-type and genetically modified mice have been essential in revealing complex cellular and molecular mechanisms that regulate thymus function. In particular, studies have demonstrated the diverse and critical role that the thymus medulla plays in shaping the peripheral T cell pool. In this review, we summarise current knowledge on functional properties of the thymus medulla that enable the thymus to support the production of diverse αβT cell types.

scholarly journals Endolymphatic Potential Measured From Developing and Adult Mouse Inner Ear

2020 ◽  
Vol 14 ◽  
Author(s):  
Yi Li ◽  
Huizhan Liu ◽  
Xiaochang Zhao ◽  
David Z. He
Keyword(s):  
Inner Ear ◽  
Hair Cells ◽  
Adult Mouse ◽  
Vestibular Function ◽  
Vestibular Organ ◽  
Positive Potential ◽  
Adult Mice ◽  
High K ◽  
Endolymphatic Potential ◽  
Vestibular Organs

The mammalian inner ear has two major parts, the cochlea is responsible for hearing and the vestibular organ is responsible for balance. The cochlea and vestibular organs are connected by a series of canals in the temporal bone and two distinct extracellular fluids, endolymph and perilymph, fill different compartments of the inner ear. Stereocilia of mechanosensitive hair cells in the cochlea and vestibular end organs are bathed in the endolymph, which contains high K+ ions and possesses a positive potential termed endolymphatic potential (ELP). Compartmentalization of the fluids provides an electrochemical gradient for hair cell mechanotransduction. In this study, we measured ELP from adult and neonatal C57BL/6J mice to determine how ELP varies and develops in the cochlear and vestibular endolymph. We measured ELP and vestibular microphonic response from saccules of neonatal mice to determine when vestibular function is mature. We show that ELP varies considerably in the cochlear and vestibular endolymph of adult mice, ranging from +95 mV in the basal turn to +87 mV in the apical turn of the cochlea, +9 mV in the saccule and utricle, and +3 mV in the semicircular canal. This suggests that ELP is indeed a local potential, despite the fact that endolymph composition is similar. We further show that vestibular ELP reaches adult-like magnitude around post-natal day 6, ~12 days earlier than maturation of cochlear ELP (i.e., endocochlear potential). Maturation of vestibular ELP coincides with the maturation of vestibular microphonic response recorded from the saccular macula, suggesting that maturation of vestibular function occurs much earlier than maturation of hearing in mice.

Classic and Novel Signaling Pathways Involved in Cancer: Targeting the NF-κB and Syk Signaling Pathways

2019 ◽  
Vol 14 (3) ◽  
pp. 219-225 ◽  
Author(s):  
Cong Tang ◽  
Guodong Zhu
Keyword(s):  
Cancer Therapy ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Cell Receptor ◽  
Transmembrane Receptors ◽  
Biological Responses ◽  
Different Types

The nuclear factor kappa B (NF-κB) consists of a family of transcription factors involved in the regulation of a wide variety of biological responses. Growing evidence support that NF-κB plays a major role in oncogenesis as well as its well-known function in the regulation of immune responses and inflammation. Therefore, we made a review of the diverse molecular mechanisms by which the NF-κB pathway is constitutively activated in different types of human cancers and the potential role of various oncogenic genes regulated by this transcription factor in cancer development and progression. We also discussed various pharmacological approaches employed to target the deregulated NF-κB signaling pathway and their possible therapeutic potential in cancer therapy. Moreover, Syk (Spleen tyrosine kinase), non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immune-receptors like the B-cell receptor (BCR), which can also activate the inflammasome and NF-κB-mediated transcription of chemokines and cytokines in the presence of pathogens would be discussed as well. The highlight of this review article is to summarize the classic and novel signaling pathways involved in NF-κB and Syk signaling and then raise some possibilities for cancer therapy.

scholarly journals Anaphylactic Degranulation of Mast Cells: Focus on Compound Exocytosis

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Ofir Klein ◽  
Ronit Sagi-Eisenberg
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Molecular Mechanisms ◽  
Secretory Granules ◽  
Cell Types ◽  
Secretory Cells ◽  
Regulated Exocytosis ◽  
Open Questions ◽  
Conflicting Evidence ◽  
Compound Exocytosis

Anaphylaxis is a notorious type 2 immune response which may result in a systemic response and lead to death. A precondition for the unfolding of the anaphylactic shock is the secretion of inflammatory mediators from mast cells in response to an allergen, mostly through activation of the cells via the IgE-dependent pathway. While mast cells are specialized secretory cells that can secrete through a variety of exocytic modes, the most predominant mode exerted by the mast cell during anaphylaxis is compound exocytosis—a specialized form of regulated exocytosis where secretory granules fuse to one another. Here, we review the modes of regulated exocytosis in the mast cell and focus on compound exocytosis. We review historical landmarks in the research of compound exocytosis in mast cells and the methods available for investigating compound exocytosis. We also review the molecular mechanisms reported to underlie compound exocytosis in mast cells and expand further with reviewing key findings from other cell types. Finally, we discuss the possible reasons for the mast cell to utilize compound exocytosis during anaphylaxis, the conflicting evidence in different mast cell models, and the open questions in the field which remain to be answered.

scholarly journals Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types

2021 ◽  
Vol 7 (3) ◽  
pp. eabd9036
Author(s):  
Sara Saez-Atienzar ◽  
Sara Bandres-Ciga ◽  
Rebekah G. Langston ◽  
Jonggeol J. Kim ◽  
Shing Wan Choi ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Membrane Trafficking ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Polygenic Risk Score ◽  
Genome Wide ◽  
Genome Wide Data ◽  
Data Driven Approach ◽  
Single Nucleus ◽  
Lateral Sclerosis

Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genome-wide data involving 78,500 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS. This data-driven approach identified multiple aspects of the biology underlying the disease that resolved into broader themes, namely, neuron projection morphogenesis, membrane trafficking, and signal transduction mediated by ribonucleotides. We also found that genomic risk in ALS maps consistently to GABAergic interneurons and oligodendrocytes, as confirmed in human single-nucleus RNA-seq data. Using two-sample Mendelian randomization, we nominated six differentially expressed genes (ATG16L2, ACSL5, MAP1LC3A, MAPKAPK3, PLXNB2, and SCFD1) within the significant pathways as relevant to ALS. We conclude that the disparate genetic etiologies of this fatal neurological disease converge on a smaller number of final common pathways and cell types.

scholarly journals In-depth transcriptomic analysis of human retina reveals molecular mechanisms underlying diabetic retinopathy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kolja Becker ◽  
Holger Klein ◽  
Eric Simon ◽  
Coralie Viollet ◽  
Christian Haslinger ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Rna Sequencing ◽  
Molecular Mechanisms ◽  
Vision Loss ◽  
Ganglion Cells ◽  
Expression Profiles ◽  
Cell Types ◽  
Sequencing Data ◽  
Disease Stages ◽  
Post Transcriptional Regulation

AbstractDiabetic Retinopathy (DR) is among the major global causes for vision loss. With the rise in diabetes prevalence, an increase in DR incidence is expected. Current understanding of both the molecular etiology and pathways involved in the initiation and progression of DR is limited. Via RNA-Sequencing, we analyzed mRNA and miRNA expression profiles of 80 human post-mortem retinal samples from 43 patients diagnosed with various stages of DR. We found differentially expressed transcripts to be predominantly associated with late stage DR and pathways such as hippo and gap junction signaling. A multivariate regression model identified transcripts with progressive changes throughout disease stages, which in turn displayed significant overlap with sphingolipid and cGMP–PKG signaling. Combined analysis of miRNA and mRNA expression further uncovered disease-relevant miRNA/mRNA associations as potential mechanisms of post-transcriptional regulation. Finally, integrating human retinal single cell RNA-Sequencing data revealed a continuous loss of retinal ganglion cells, and Müller cell mediated changes in histidine and β-alanine signaling. While previously considered primarily a vascular disease, attention in DR has shifted to additional mechanisms and cell-types. Our findings offer an unprecedented and unbiased insight into molecular pathways and cell-specific changes in the development of DR, and provide potential avenues for future therapeutic intervention.

scholarly journals MicroRNAs and Stem-like Properties: The Complex Regulation Underlying Stemness Maintenance and Cancer Development

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1074
Author(s):  
Giuseppina Divisato ◽  
Silvia Piscitelli ◽  
Mariantonietta Elia ◽  
Emanuela Cascone ◽  
Silvia Parisi
Keyword(s):  
Stem Cells ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Embryonic Stem ◽  
Cell Types ◽  
Cancer Development ◽  
Special Focus ◽  
Self Renewal ◽  
Mesenchymal Transition ◽  
Different Cell Types

Embryonic stem cells (ESCs) have the extraordinary properties to indefinitely proliferate and self-renew in culture to produce different cell progeny through differentiation. This latter process recapitulates embryonic development and requires rounds of the epithelial–mesenchymal transition (EMT). EMT is characterized by the loss of the epithelial features and the acquisition of the typical phenotype of the mesenchymal cells. In pathological conditions, EMT can confer stemness or stem-like phenotypes, playing a role in the tumorigenic process. Cancer stem cells (CSCs) represent a subpopulation, found in the tumor tissues, with stem-like properties such as uncontrolled proliferation, self-renewal, and ability to differentiate into different cell types. ESCs and CSCs share numerous features (pluripotency, self-renewal, expression of stemness genes, and acquisition of epithelial–mesenchymal features), and most of them are under the control of microRNAs (miRNAs). These small molecules have relevant roles during both embryogenesis and cancer development. The aim of this review was to recapitulate molecular mechanisms shared by ESCs and CSCs, with a special focus on the recently identified classes of microRNAs (noncanonical miRNAs, mirtrons, isomiRs, and competitive endogenous miRNAs) and their complex functions during embryogenesis and cancer development.

scholarly journals Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens

2021 ◽  
Author(s):  
Hee-Dae Kim ◽  
Jing Wei ◽  
Tanessa Call ◽  
Nicole Teru Quintus ◽  
Alexander J. Summers ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Current Treatment ◽  
Specific Cell ◽  
Excitatory Synapses ◽  
Cell Type ◽  
Cell Type Specific ◽  
Specific Regulation ◽  
Circuit Function

AbstractDepression is the leading cause of disability and produces enormous health and economic burdens. Current treatment approaches for depression are largely ineffective and leave more than 50% of patients symptomatic, mainly because of non-selective and broad action of antidepressants. Thus, there is an urgent need to design and develop novel therapeutics to treat depression. Given the heterogeneity and complexity of the brain, identification of molecular mechanisms within specific cell-types responsible for producing depression-like behaviors will advance development of therapies. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activity of D1- or D2- medium spiny neurons (MSNs). Here we report a circuit- and cell-type specific molecular target for depression, Shisa6, recently defined as an AMPAR component, which is increased only in D1-MSNs in the NAc of susceptible mice. Using the Ribotag approach, we dissected the transcriptional profile of D1- and D2-MSNs by RNA sequencing following a mouse model of depression, chronic social defeat stress (CSDS). Bioinformatic analyses identified cell-type specific genes that may contribute to the pathogenesis of depression, including Shisa6. We found selective optogenetic activation of the ventral tegmental area (VTA) to NAc circuit increases Shisa6 expression in D1-MSNs. Shisa6 is specifically located in excitatory synapses of D1-MSNs and increases excitability of neurons, which promotes anxiety- and depression-like behaviors in mice. Cell-type and circuit-specific action of Shisa6, which directly modulates excitatory synapses that convey aversive information, identifies the protein as a potential rapid-antidepressant target for aberrant circuit function in depression.

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