scholarly journals Fibronectin splice variants: Understanding their multiple roles in health and disease using engineered mouse models

IUBMB Life ◽  
2011 ◽  
Vol 63 (7) ◽  
pp. 538-546 ◽  
Author(s):  
Eric S. White ◽  
Andrés F. Muro
Keyword(s):  
Mouse Models ◽  
Splice Variants ◽  
Multiple Roles ◽  
Health And Disease

scholarly journals Expression of Cholinergic Markers and Characterization of Splice Variants during Ontogenesis of Rat Dorsal Root Ganglia Neurons

2021 ◽  
Vol 22 (11) ◽  
pp. 5499
Author(s):  
Veronica Corsetti ◽  
Carla Perrone-Capano ◽  
Michael Sebastian Salazar Intriago ◽  
Elisabetta Botticelli ◽  
Giancarlo Poiana ◽  
...  
Keyword(s):  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Splice Variants ◽  
Multiple Roles ◽  
Pcr Analysis ◽  
Drg Neurons ◽  
Embryonic Developmental Stage ◽  
Embryo Stage ◽  
Dorsal Root Ganglia Neurons ◽  
Cholinergic Markers

Dorsal root ganglia (DRG) neurons synthesize acetylcholine (ACh), in addition to their peptidergic nature. They also release ACh and are cholinoceptive, as they express cholinergic receptors. During gangliogenesis, ACh plays an important role in neuronal differentiation, modulating neuritic outgrowth and neurospecific gene expression. Starting from these data, we studied the expression of choline acetyltransferase (ChAT) and vesicular ACh transporter (VAChT) expression in rat DRG neurons. ChAT and VAChT genes are arranged in a “cholinergic locus”, and several splice variants have been described. Using selective primers, we characterized splice variants of these cholinergic markers, demonstrating that rat DRGs express R1, R2, M, and N variants for ChAT and V1, V2, R1, and R2 splice variants for VAChT. Moreover, by RT-PCR analysis, we observed a progressive decrease in ChAT and VAChT transcripts from the late embryonic developmental stage (E18) to postnatal P2 and P15 and in the adult DRG. Interestingly, Western blot analyses and activity assays demonstrated that ChAT levels significantly increased during DRG ontogenesis. The modulated expression of different ChAT and VAChT splice variants during development suggests a possible differential regulation of cholinergic marker expression in sensory neurons and confirms multiple roles for ACh in DRG neurons, both in the embryo stage and postnatally.

scholarly journals Generation, quality control, and analysis of the first genomically humanised knock-in mice for the ALS/FTD genes SOD1, TARDBP (TDP-43), and FUS

2021 ◽  
Author(s):  
Anny Devoy ◽  
Georgia Price ◽  
Francesca De Giorgio ◽  
Rosie Bunton-Stasyshyn ◽  
David Thompson ◽  
...  
Keyword(s):  
Quality Control ◽  
Mouse Models ◽  
Splice Variants ◽  
Region Of Interest ◽  
Human Protein ◽  
Mouse Strains ◽  
Coding Region ◽  
Protein Biochemistry ◽  
Oxford Nanopore

Amyotrophic lateral sclerosis - frontotemporal dementia spectrum disorder (ALS/FTD) is a complex neurodegenerative disease; up to 10% of cases are familial, usually arising from single dominant mutations in >30 causative genes. Transgenic mouse models that overexpress human ALS/FTD causative genes have been the preferred organism for in vivo modelling. However, while conferring human protein biochemistry, these overexpression models are not ideal for dosage-sensitive proteins such as TDP-43 or FUS. We have created three next-generation genomically humanised knock-in mouse models for ALS/FTD research, by replacing the entire mouse coding region of Sod1, Tardbp (TDP-43) and Fus, with their human orthologues to preserve human protein biochemistry, with exons and introns intact to enable future modelling of coding or non-coding mutations and variants and to preserve human splice variants. In generating these mice, we have established a new-standard of quality control: we demonstrate the utility of indirect capture for enrichment of a region of interest followed by Oxford Nanopore sequencing for robustly characterising large knock-in alleles. This approach confirmed that targeting occurred at the correct locus and to map homologous recombination events. Furthermore, extensive expression data from the three lines shows that homozygous humanised animals only express human protein, at endogenous levels. Characterisation of humanised FUS animals showed that they are phenotypically normal compared to wildtype littermates throughout their lifespan. These humanised mouse strains are critically needed for preclinical assessment of interventions, such as antisense oligonucleotides (ASOs), to modulate expression levels in patients, and will serve as templates for the addition of human ALS/FTD mutations to dissect disease pathomechanisms.

Dipeptidyl peptidase (DP) 6 and DP10: novel brain proteins implicated in human health and disease

2009 ◽  
Vol 47 (3) ◽  
Author(s):  
Kym McNicholas ◽  
Tong Chen ◽  
Catherine A. Abbott
Keyword(s):  
Human Health ◽  
Splice Variants ◽  
Dipeptidyl Peptidase ◽  
Fibroblast Activation Protein ◽  
Voltage Gated ◽  
Kv Channels ◽  
Cellular Excitability ◽  
Kv4 Channels ◽  
Health And Disease ◽  
Critical Components

AbstractDipeptidyl peptidase (DP) 6 and DP10 are non-enzyme members of the dipeptidyl peptidase IV family, which includes fibroblast activation protein, DP8, and DP9. DP6 and DP10 proteins have been shown to be critical components of voltage-gated potassium (Kv) channels important in determining cellular excitability. The aim of this paper was to review the research to date on DP6 and DP10 structure, expression, and functions. To date, the protein region responsible for modulating Kv4 channels has not been conclusively identified and the significance of the splice variants has not been resolved. Resolution of these issues will improve our overall knowledge of DP6 and DP10 and lead to a better understanding of their role in diseases, such as asthma and Alzheimer's disease.Clin Chem Lab Med 2009;47:262–7.

Multiple roles of FOXJ3 in spermatogenesis: A lesson fromFoxj3conditional knockout mouse models

2016 ◽  
Vol 83 (12) ◽  
pp. 1060-1069 ◽  
Author(s):  
Lili Ni ◽  
Hongchang Xie ◽  
Li Tan
Keyword(s):  
Mouse Models ◽  
Knockout Mouse ◽  
Multiple Roles

scholarly journals Revisiting the multiple roles of T-cadherin in health and disease

2021 ◽  
pp. 151183
Author(s):  
K.A. Rubina ◽  
E.V. Semina ◽  
N.I. Kalinina ◽  
Sysoeva V. Yu ◽  
A.V. Balatskiy ◽  
...  
Keyword(s):  
Multiple Roles ◽  
Health And Disease

scholarly journals Proteoglycans in health and disease: the multiple roles of syndecan shedding

FEBS Journal ◽  
2010 ◽  
Vol 277 (19) ◽  
pp. 3876-3889 ◽  
Author(s):  
Tina Manon-Jensen ◽  
Yoshifumi Itoh ◽  
John R. Couchman
Keyword(s):  
Multiple Roles ◽  
Health And Disease

scholarly journals Splice Variant-Dependent Regulation of β-Cell Sodium-Calcium Exchange by Acyl-Coenzyme As

2008 ◽  
Vol 22 (10) ◽  
pp. 2293-2306 ◽  
Author(s):  
Kevin S. C. Hamming ◽  
Michael J. Riedel ◽  
Daniel Soliman ◽  
Laura C. Matemisz ◽  
Nicola J. Webster ◽  
...  
Keyword(s):  
Splice Variant ◽  
Splice Variants ◽  
Degree Of Saturation ◽  
Sodium Calcium Exchanger ◽  
Biophysical Properties ◽  
Β Cell ◽  
Sodium Calcium ◽  
Chain Acyl ◽  
Health And Disease ◽  
Long Chain

Abstract The sodium-calcium exchanger isoform 1 (NCX1) is intimately involved in the regulation of calcium (Ca2+) homeostasis in many tissues including excitation-secretion coupling in pancreatic β-cells. Our group has previously found that intracellular long-chain acyl-coenzyme As (acyl CoAs) are potent regulators of the cardiac NCX1.1 splice variant. Despite this, little is known about the biophysical properties of β-cell NCX1 splice variants and the effects of intracellular modulators on their important physiological function in health and disease. Here, we show that the forward-mode activity of β-cell NCX1 splice variants is differentially modulated by acyl-CoAs and is dependent both upon the intrinsic biophysical properties of the particular NCX1 splice variant as well as the side chain length and degree of saturation of the acyl-CoA moiety. Notably, saturated long-chain acyl-CoAs increased both peak and total NCX1 activity, whereas polyunsaturated long-chain acyl-CoAs did not show this effect. Furthermore, we have identified the exon within the alternative splicing region that bestows sensitivity to acyl-CoAs. We conclude that the physiologically relevant forward-mode activity of NCX1 splice variants expressed in the pancreatic β-cell are sensitive to acyl-CoAs of different saturation and alterations in intracellular acyl-CoA levels may ultimately lead to defects in Ca2+-mediated exocytosis and insulin secretion.

scholarly journals Nitric Oxide in Health and Disease of the Respiratory System

2004 ◽  
Vol 84 (3) ◽  
pp. 731-765 ◽  
Author(s):  
Fabio L. M. Ricciardolo ◽  
Peter J. Sterk ◽  
Benjamin Gaston ◽  
Gert Folkerts
Keyword(s):  
Nitric Oxide ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Multiple Roles ◽  
Major Advance ◽  
Airway Diseases ◽  
Exhaled Air ◽  
Health And Disease ◽  
Novel Target ◽  
Airway Physiology

During the past decade a plethora of studies have unravelled the multiple roles of nitric oxide (NO) in airway physiology and pathophysiology. In the respiratory tract, NO is produced by a wide variety of cell types and is generated via oxidation of l-arginine that is catalyzed by the enzyme NO synthase (NOS). NOS exists in three distinct isoforms: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). NO derived from the constitutive isoforms of NOS (nNOS and eNOS) and other NO-adduct molecules (nitrosothiols) have been shown to be modulators of bronchomotor tone. On the other hand, NO derived from iNOS seems to be a proinflammatory mediator with immunomodulatory effects. The concentration of this molecule in exhaled air is abnormal in activated states of different inflammatory airway diseases, and its monitoring is potentially a major advance in the management of, e.g., asthma. Finally, the production of NO under oxidative stress conditions secondarily generates strong oxidizing agents (reactive nitrogen species) that may modulate the development of chronic inflammatory airway diseases and/or amplify the inflammatory response. The fundamental mechanisms driving the altered NO bioactivity under pathological conditions still need to be fully clarified, because their regulation provides a novel target in the prevention and treatment of chronic inflammatory diseases of the airways.

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