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Tal Hoffmann, Ohad Sharon, Jürgen Wittmann, Richard W Carr, Alina Vyshnevska, Roberto De Col, Mohammed A Nassar, Peter W Reeh, Christian Weidner
The sodium channel NaV1.7 contributes to action potential (AP) generation and propagation. Loss-of-function mutations in patients lead to congenital indifference to pain, though it remains unclear where on the way from sensory terminals to central nervous system the signalling is disrupted. We confirm that conditional deletion of NaV1.7 in advillin-expressing sensory neurons leads to impaired heat and mechanical nociception in behavioural tests. With single-fiber recordings from isolated skin, we found (1) a significantly lower prevalence of heat responsiveness to normally mechanosensitive C-fibers, although (2) the rare heat responses seemed quite vigorous, and (3) heat-induced calcitonin gene-related peptide release was normal...
March 2018: Pain
Jia Rao, Shazia Ashraf, Weizhen Tan, Amelie T van der Ven, Heon Yung Gee, Daniela A Braun, Krisztina Fehér, Sudeep P George, Amin Esmaeilniakooshkghazi, Won-Il Choi, Tilman Jobst-Schwan, Ronen Schneider, Johanna Magdalena Schmidt, Eugen Widmeier, Jillian K Warejko, Tobias Hermle, David Schapiro, Svjetlana Lovric, Shirlee Shril, Ankana Daga, Ahmet Nayir, Mohan Shenoy, Yincent Tse, Martin Bald, Udo Helmchen, Sevgi Mir, Afig Berdeli, Jameela A Kari, Sherif El Desoky, Neveen A Soliman, Arvind Bagga, Shrikant Mane, Mohamad A Jairajpuri, Richard P Lifton, Seema Khurana, Jose C Martins, Friedhelm Hildebrandt
Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of chronic kidney disease. Here, we identified recessive mutations in the gene encoding the actin-binding protein advillin (AVIL) in 3 unrelated families with SRNS. While all AVIL mutations resulted in a marked loss of its actin-bundling ability, truncation of AVIL also disrupted colocalization with F-actin, thereby leading to impaired actin binding and severing. Additionally, AVIL colocalized and interacted with the phospholipase enzyme PLCE1 and with the ARP2/3 actin-modulating complex...
October 23, 2017: Journal of Clinical Investigation
Douglas M Lopes, Franziska Denk, Stephen B McMahon
The dorsal root ganglia (DRG) and trigeminal ganglia (TG) are clusters of cell bodies of highly specialized sensory neurons which are responsible for relaying information about our environment to the central nervous system. Despite previous efforts to characterize sensory neurons at the molecular level, it is still unknown whether those present in DRG and TG have distinct expression profiles and therefore a unique molecular fingerprint. To address this question, we isolated lumbar DRG and TG neurons using fluorescence-activated cell sorting from Advillin-GFP transgenic mice and performed RNA sequencing...
2017: Frontiers in Molecular Neuroscience
Katherine J Zappia, Crystal L O'Hara, Francie Moehring, Kelvin Y Kwan, Cheryl L Stucky
The nonselective cation channel transient receptor potential ankyrin 1 (TRPA1) is known to be a key contributor to both somatosensation and pain. Recent studies have implicated TRPA1 in additional physiologic functions and have also suggested that TRPA1 is expressed in nonneuronal tissues. Thus, it has become necessary to resolve the importance of TRPA1 expressed in primary sensory neurons, particularly since previous research has largely used global knock-out animals and chemical TRPA1 antagonists. We therefore sought to isolate the physiological relevance of TRPA1 specifically within sensory neurons...
January 2017: ENeuro
Pu-Hong He, Wei-Xia Dong, Xin-Ling Chu, Ming-Guang Feng, Sheng-Hua Ying
The gelsolin superfamily includes seven protein members: gelsolin, villin, adseverin, CapG, advillin, supervillin and flightless I. The gelsolin proteins are actin-binding proteins that contain three or six gelsolin-like domains, and they play important roles in remodelling actin dynamics and cellular processes in eukaryotes. The entomopathogenic fungus Beauveria bassiana expresses a unique CapG protein (BbGEL1) that contains three gelsolin-like domains. BbGEL1p is associated with actin during mycelial growth and plays an important role in fungal morphological transitions under both aerobic and submerged conditions...
November 2016: Environmental Microbiology
Elena Neumann, Timo Brandenburger, Sonia Santana-Varela, René Deenen, Karl Köhrer, Inge Bauer, Henning Hermanns, John N Wood, Jing Zhao, Robert Werdehausen
BACKGROUND: MicroRNAs (miRNAs) regulate gene expression in physiological as well as in pathological processes, including chronic pain. Whether deletion of a gene can affect expression of the miRNAs that associate with the deleted gene mRNA remains elusive. We investigated the effects of brain-derived neurotrophic factor (Bdnf) gene deletion on the expression of miR-1 in dorsal root ganglion (DRG) neurons and its pain-associated downstream targets heat shock protein 60 (Hsp60) and connexin 43 (Cx43) in tamoxifen-inducible conditional knockout mice, Bdnf(fl/fl); Advillin-CreER(T2) (Bdnf cKO)...
September 2016: Molecular and Cellular Neurosciences
Bin Feng, Sonali C Joyce, G F Gebhart
The sensory innervation of the distal colorectum includes mechanically insensitive afferents (MIAs; ∼25%), which acquire mechanosensitivity in persistent visceral hypersensitivity and thus generate de novo input to the central nervous system. We utilized an optogenetic approach to bypass the process of transduction (generator potential) and focus on transformation (spike initiation) at colorectal MIA sensory terminals, which is otherwise not possible in typical functional studies. From channelrhodopsin2-expressing mice (driven by Advillin-Cre), the distal colorectum with attached pelvic nerve was harvested for ex vivo single-fiber recordings...
May 15, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
Byeongjun Lee, Hawon Cho, Jooyoung Jung, Young Duk Yang, Dong-Jin Yang, Uhtaek Oh
BACKGROUND: Various pathological conditions such as inflammation or injury can evoke pain hypersensitivity. That represents the response to innocuous stimuli or exaggerated response to noxious stimuli. The molecular mechanism based on the pain hypersensitivity is associated with changes in many of ion channels in dorsal-root ganglion (DRG) neurons. Anoctamin 1 (ANO1/TMEM16A), a Ca2+ activated chloride channel is highly visible in small DRG neurons and responds to heat. Mice with an abolished function of ANO1 in DRG neurons demonstrated attenuated pain-like behaviors when exposed to noxious heat, suggesting a role in acute thermal nociception...
2014: Molecular Pain
Umesh Ghoshdastider, David Popp, Leslie D Burtnick, Robert C Robinson
The gelsolin homology (GH) domain has been found to date exclusively in actin-binding proteins. In humans, three copies of the domain are present in CapG, five copies in supervillin, and six copies each in adseverin, gelsolin, flightless I and the villins: villin, advillin and villin-like protein. Caenorhabditis elegans contains a four-GH-domain protein, GSNL-1. These architectures are predicted to have arisen from gene triplication followed by gene duplication to result in the six-domain protein. The subsequent loss of one, two or three domains produced the five-, four-, and three-domain proteins, respectively...
November 2013: Cytoskeleton
Promila Pagadala, Chul-Kyu Park, Sangsu Bang, Zheng-Zhong Xu, Rou-Gang Xie, Tong Liu, Bao-Xia Han, W Daniel Tracey, Fan Wang, Ru-Rong Ji
It is well established that activation of NMDARs plays an essential role in spinal cord synaptic plasticity (i.e., central sensitization) and pain hypersensitivity after tissue injury. Despite prominent expression of NMDARs in DRG primary sensory neurons, the unique role of peripheral NMDARs in regulating intrinsic neuronal excitability and pain sensitivity is not well understood, in part due to the lack of selective molecular tools. To address this problem, we used Advillin-Cre driver to delete the NR1 subunit of NMDARs selectively in DRG neurons...
August 14, 2013: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Shalini Nag, Mårten Larsson, Robert C Robinson, Leslie D Burtnick
Gelsolin superfamily members are Ca(2+) -dependent, multidomain regulators of the actin cytoskeleton. Calcium binding activates gelsolin by inducing molecular gymnastics (large-scale conformational changes) that expose actin interaction surfaces by releasing a series of latches. A specialized tail latch has distinguished gelsolin within the superfamily. Active gelsolin exhibits actin filament severing and capping, and actin monomer sequestering activities. Here, we analyze a combination of sequence, structural, biophysical and biochemical data to assess whether the molecular plasticity, regulation and actin-related properties of gelsolin are also present in other superfamily members...
July 2013: Cytoskeleton
Michael S Minett, Mohammed A Nassar, Anna K Clark, Gayle Passmore, Anthony H Dickenson, Fan Wang, Marzia Malcangio, John N Wood
Human acute and inflammatory pain requires the expression of voltage-gated sodium channel Nav1.7 but its significance for neuropathic pain is unknown. Here we show that Nav1.7 expression in different sets of mouse sensory and sympathetic neurons underlies distinct types of pain sensation. Ablating Nav1.7 gene (SCN9A) expression in all sensory neurons using Advillin-Cre abolishes mechanical pain, inflammatory pain and reflex withdrawal responses to heat. In contrast, heat-evoked pain is retained when SCN9A is deleted only in Nav1...
April 24, 2012: Nature Communications
Joanne Lau, Michael S Minett, Jing Zhao, Ulla Dennehy, Fan Wang, John N Wood, Yury D Bogdanov
BACKGROUND: Tissue-specific gene deletion has proved informative in the analysis of pain pathways. Advillin has been shown to be a pan-neuronal marker of spinal and cranial sensory ganglia. We generated BAC transgenic mice using the Advillin promoter to drive a tamoxifen-inducible CreERT2 recombinase construct in order to be able to delete genes in adult animals. We used a floxed stop ROSA26LacZ reporter mouse to examine functional Cre expression, and analysed the behaviour of mice expressing Cre recombinase...
December 21, 2011: Molecular Pain
Paul Jennings, Christina Weiland, Alice Limonciel, Katarzyna M Bloch, Robert Radford, Lydia Aschauer, Tara McMorrow, Anja Wilmes, Walter Pfaller, Hans J Ahr, Craig Slattery, Edward A Lock, Michael P Ryan, Heidrun Ellinger-Ziegelbauer
Ochratoxin A (OTA) is a widely studied compound due to its role in renal toxicity and carcinogenicity. However, there is still no consensus on the exact mechanisms of toxicity or carcinogenicity. In the current study, we analysed the effect of OTA on three human renal proximal tubular models (human primary, RPTEC/TERT1 and HK-2 cells) and two rat renal proximal tubular models (rat primary and NRK-52E cells). Global transcriptomics analysis at two exposure times was performed to generate a set of 756 OTA sensitive genes...
April 2012: Archives of Toxicology
Sandra Zurborg, Agnieszka Piszczek, Conception Martínez, Philip Hublitz, Mumna Al Banchaabouchi, Pedro Moreira, Emerald Perlas, Paul A Heppenstall
Progress in the somatosensory field has been restricted by the limited number of genetic tools available to study gene function in peripheral sensory neurons. Here we generated a Cre-driver mouse line that expresses Cre-recombinase from the locus of the sensory neuron specific gene Advillin. These mice displayed almost exclusive Cre-mediated recombination in all peripheral sensory neurons. As such, the Advillin-Cre-driver line will be a powerful tool for targeting peripheral neurons in future investigations...
2011: Molecular Pain
Stefano Piana, Alessandro Laio
All-atom explicit-solvent molecular dynamics simulations have been used to investigate the topological structure of the space explored during folding by the c-terminal fragment of the Advillin headpiece, a 36 amino-acid protein. A fractal dimension analysis shows that the hypersurface explored during the folding process has an approximate dimensionality of only three. It is shown that this low dimensionality persists well above the unfolding temperature and is not present in simple coarse-grained models.
November 14, 2008: Physical Review Letters
Hiroshi Hasegawa, Sara Abbott, Bao-Xia Han, Yi Qi, Fan Wang
Peripheral sensory neurons detect diverse physical stimuli and transmit the information into the CNS. At present, the genetic tools for specifically studying the development, plasticity, and regeneration of the sensory axon projections are limited. We found that the gene encoding Advillin, an actin binding protein that belongs to the gelsolin superfamily, is expressed almost exclusively in peripheral sensory neurons. We next generated a line of knock-in mice in which the start codon of the Advillin is replaced by the gene encoding human placenta alkaline phosphatase (Avil-hPLAP mice)...
December 26, 2007: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Stefano Piana, Alessandro Laio, Fabrizio Marinelli, Marleen Van Troys, David Bourry, Christophe Ampe, José C Martins
Homology modeling of unknown proteins is based on the assumption that highly similar sequences are likely to share the same fold. However, this does not provide any information on the stability of a given fold, which is ultimately determined by the subtle interplay of enthalpic and entropic contributions. Herein it is shown that ab initio atomistic simulations can be used to predict the effect of point mutations on the stability of a protein fold. The calculations indicate that the fold stabilities of two proteins of similar sequence and identical fold, the villin and advillin C-terminal headpiece fragments, are different and that the same P62A point mutation has a dramatic effect on the fold of villin but a minor one on that of advillin...
January 11, 2008: Journal of Molecular Biology
Junko Ishii, Hideki Adachi, Norihito Shibata, Hiroyuki Arai, Masafumi Tsujimoto
The scavenger receptor expressed by endothelial cells (SREC)-I was originally identified in a human endothelial cell line by expression cloning. Subsequently it was shown that the cytoplasmic domain of SREC-I mediates the neurite-like outgrowth of murine fibroblastic L cells through interaction with advillin, a member of gelsolin/villin family of actin regulatory proteins. In this work, we further searched for a binding protein to the cytoplasmic domain of the receptor, which might be required for the morphological change of L cells and identified protein phosphatase 1alpha (PP1alpha) as a binding protein to this domain...
August 17, 2007: Biochemical and Biophysical Research Communications
Alan C Love, Mary E Andrews, Rudolf A Raff
The larval arms of echinoid plutei are used for locomotion and feeding. They are composed of internal calcite skeletal rods covered by an ectoderm layer bearing a ciliary band. Skeletogenesis includes an autonomous molecular differentiation program in primary mesenchyme cells (PMCs), initiated when PMCs leave the vegetal plate for the blastocoel, and a patterning of the differentiated skeletal units that requires molecular cues from the overlaying ectoderm. The arms represent a larval feature that arose in the echinoid lineage during the Paleozoic and offers a subject for the study of gene co-option in the evolution of novel larval features...
January 2007: Evolution & Development
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