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Open Access Articles

2015

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Articles 1 - 20 of 20

Full-Text Articles in Cell Biology

Ggggcc Microsatellite Rna Is Neuritically Localized, Induces Branching Defects, And Perturbs Transport Granule Function, Alondra Schweizer Burguete, Sandra Almeida, Fen-Biao Gao, Robert Kalb, Michael R. Akins, Nancy M. Bonini Dec 2015

Ggggcc Microsatellite Rna Is Neuritically Localized, Induces Branching Defects, And Perturbs Transport Granule Function, Alondra Schweizer Burguete, Sandra Almeida, Fen-Biao Gao, Robert Kalb, Michael R. Akins, Nancy M. Bonini

Open Access Articles

Microsatellite expansions are the leading cause of numerous neurodegenerative disorders. Here we demonstrate that GGGGCC and CAG microsatellite repeat RNAs associated with C9orf72 in ALS/FTD and with polyglutamine diseases, respectively, localize to neuritic granules that undergo active transport into distal neuritic segments. In cultured mammalian spinal cord neurons, the presence of neuritic GGGGCC repeat RNA correlates with neuronal branching defects and the repeat RNA localizes to granules that label with FMRP, a transport granule component. Using a Drosophila GGGGCC expansion disease model, we characterize dendritic branching defects that are modulated by FMRP and Orb2. The human orthologues of these ...


Near-Infrared Photoactivatable Control Of Ca Signaling And Optogenetic Immunomodulation, Lian He, Yuanwei Zhang, Guolin Ma, Peng Tan, Zhan Jun Li, Shengbing Zhang, Xiang Wu, Ji Jing, Shaohai Fang, Lijuan Zhou, Youjun Wang, Yun Huang, Patrick Hogan, Gang Han, Yubin Zhou Dec 2015

Near-Infrared Photoactivatable Control Of Ca Signaling And Optogenetic Immunomodulation, Lian He, Yuanwei Zhang, Guolin Ma, Peng Tan, Zhan Jun Li, Shengbing Zhang, Xiang Wu, Ji Jing, Shaohai Fang, Lijuan Zhou, Youjun Wang, Yun Huang, Patrick Hogan, Gang Han, Yubin Zhou

Open Access Articles

The application of current channelrhodopsin-based optogenetic tools is limited by the lack of strict ion selectivity and the inability to extend the spectra sensitivity into the near-infrared (NIR) tissue transmissible range. Here we present an NIR-stimulable optogenetic platform (termed "Opto-CRAC") that selectively and remotely controls Ca2+ oscillations and Ca2+-responsive gene expression to regulate the function of non-excitable cells, including T lymphocytes, macrophages and dendritic cells. When coupled to upconversion nanoparticles, the optogenetic operation window is shifted from the visible range to NIR wavelengths to enable wireless photoactivation of Ca2+-dependent signaling and optogenetic modulation of immunoinflammatory responses. In a ...


Bunched And Madm Function Downstream Of Tuberous Sclerosis Complex To Regulate The Growth Of Intestinal Stem Cells In Drosophila, Yingchao Nie, Qi Li, Alla Amcheslavsky, Juan Carlos Duhart, Alexey Veraksa, Hugo Stocker, Laurel A. Raftery, Y. Tony Ip Dec 2015

Bunched And Madm Function Downstream Of Tuberous Sclerosis Complex To Regulate The Growth Of Intestinal Stem Cells In Drosophila, Yingchao Nie, Qi Li, Alla Amcheslavsky, Juan Carlos Duhart, Alexey Veraksa, Hugo Stocker, Laurel A. Raftery, Y. Tony Ip

Open Access Articles

The Drosophila adult midgut contains intestinal stem cells that support homeostasis and repair. We show here that the leucine zipper protein Bunched and the adaptor protein Madm are novel regulators of intestinal stem cells. MARCM mutant clonal analysis and cell type specific RNAi revealed that Bunched and Madm were required within intestinal stem cells for proliferation. Transgenic expression of a tagged Bunched showed a cytoplasmic localization in midgut precursors, and the addition of a nuclear localization signal to Bunched reduced its function to cooperate with Madm to increase intestinal stem cell proliferation. Furthermore, the elevated cell growth and 4EBP phosphorylation ...


Membrane-Bound And Soluble Fas Ligands Have Opposite Functions In Photoreceptor Cell Death Following Separation From The Retinal Pigment Epithelium, H. Matsumoto, Y. Murakami, K. Kataoka, S. Notomi, D. Mantopoulos, G. Trichonas, J. W. Miller, M. S. Gregory, B R. Ksander, Ann Marshak-Rothstein, D. G. Vavvas Nov 2015

Membrane-Bound And Soluble Fas Ligands Have Opposite Functions In Photoreceptor Cell Death Following Separation From The Retinal Pigment Epithelium, H. Matsumoto, Y. Murakami, K. Kataoka, S. Notomi, D. Mantopoulos, G. Trichonas, J. W. Miller, M. S. Gregory, B R. Ksander, Ann Marshak-Rothstein, D. G. Vavvas

Open Access Articles

Fas ligand (FasL) triggers apoptosis of Fas-positive cells, and previous reports described FasL-induced cell death of Fas-positive photoreceptors following a retinal detachment. However, as FasL exists in membrane-bound (mFasL) and soluble (sFasL) forms, and is expressed on resident microglia and infiltrating monocyte/macrophages, the current study examined the relative contribution of mFasL and sFasL to photoreceptor cell death after induction of experimental retinal detachment in wild-type, knockout (FasL-/-), and mFasL-only knock-in (DeltaCS) mice. Retinal detachment in FasL-/- mice resulted in a significant reduction of photoreceptor cell death. In contrast, DeltaCS mice displayed significantly more apoptotic photoreceptor cell death. Photoreceptor loss ...


Current Questions And Possible Controversies In Autophagy, L M. Lindqvist, A K. Simon, Eric H. Baehrecke Nov 2015

Current Questions And Possible Controversies In Autophagy, L M. Lindqvist, A K. Simon, Eric H. Baehrecke

Open Access Articles

Interest in autophagy has exploded over the last decade, with publications highlighting crosstalk with several other cellular processes including secretion, endocytosis, and cell suicide pathways including apoptosis. Autophagy proteins have also been implicated in other cellular processes independently of their roles in autophagy, creating complexities in the interpretation of autophagy (Atg) mutant gene data. Interestingly, this self-eating process is a survival mechanism that can also promote cell death, but when and how autophagy may 'switch' its function is still under debate. Indeed, there are currently many models of how autophagy actually influences cell death. In this review, we highlight some ...


Positioning Of Ampa Receptor-Containing Endosomes Regulates Synapse Architecture, Marta Esteves Da Silva, Max Adrian, Philipp Schatzle, Joanna Lipka, Takuya Watanabe, Sukhee Cho, Kensuke Futai, Corette J. Wierenga, Lukas C. Kapitein, Casper C. Hoogenraad Nov 2015

Positioning Of Ampa Receptor-Containing Endosomes Regulates Synapse Architecture, Marta Esteves Da Silva, Max Adrian, Philipp Schatzle, Joanna Lipka, Takuya Watanabe, Sukhee Cho, Kensuke Futai, Corette J. Wierenga, Lukas C. Kapitein, Casper C. Hoogenraad

Open Access Articles

Lateral diffusion in the membrane and endosomal trafficking both contribute to the addition and removal of AMPA receptors (AMPARs) at postsynaptic sites. However, the spatial coordination between these mechanisms has remained unclear, because little is known about the dynamics of AMPAR-containing endosomes. In addition, how the positioning of AMPAR-containing endosomes affects synapse organization and functioning has never been directly explored. Here, we used live-cell imaging in hippocampal neuron cultures to show that intracellular AMPARs are transported in Rab11-positive recycling endosomes, which frequently enter dendritic spines and depend on the microtubule and actin cytoskeleton. By using chemically induced dimerization systems to ...


Regulation Of Nucleosome Architecture And Factor Binding Revealed By Nuclease Footprinting Of The Esc Genome, Sarah J. Hainer, Thomas G. Fazzio Oct 2015

Regulation Of Nucleosome Architecture And Factor Binding Revealed By Nuclease Footprinting Of The Esc Genome, Sarah J. Hainer, Thomas G. Fazzio

Open Access Articles

Functional interactions between gene regulatory factors and chromatin architecture have been difficult to directly assess. Here, we use micrococcal nuclease (MNase) footprinting to probe the functions of two chromatin-remodeling complexes. By simultaneously quantifying alterations in small MNase footprints over the binding sites of 30 regulatory factors in mouse embryonic stem cells (ESCs), we provide evidence that esBAF and Mbd3/NuRD modulate the binding of several regulatory proteins. In addition, we find that nucleosome occupancy is reduced at specific loci in favor of subnucleosomes upon depletion of esBAF, including sites of histone H2A.Z localization. Consistent with these data, we demonstrate ...


Extracellular Rnas: Development As Biomarkers Of Human Disease, Joseph F. Quinn, Tushar Patel, David Wong, Saumya Das, Jane Freedman, Louise C. Laurent, Bob S. Carter, Fred Hochberg, Julie A. Saugstad Aug 2015

Extracellular Rnas: Development As Biomarkers Of Human Disease, Joseph F. Quinn, Tushar Patel, David Wong, Saumya Das, Jane Freedman, Louise C. Laurent, Bob S. Carter, Fred Hochberg, Julie A. Saugstad

Open Access Articles

Ten ongoing studies designed to test the possibility that extracellular RNAs may serve as biomarkers in human disease are described. These studies, funded by the NIH Common Fund Extracellular RNA Communication Program, examine diverse extracellular body fluids, including plasma, serum, urine and cerebrospinal fluid. The disorders studied include hepatic and gastric cancer, cardiovascular disease, chronic kidney disease, neurodegenerative disease, brain tumours, intracranial haemorrhage, multiple sclerosis and placental disorders. Progress to date and the plans for future studies are outlined.


Meeting Report: Discussions And Preliminary Findings On Extracellular Rna Measurement Methods From Laboratories In The Nih Extracellular Rna Communication Consortium, Louise C. Laurent, Asim B. Abdel-Mageed, P. David Adelson, Jorge Arango, Leonora Balaj, Xandra Breakefield, Elizabeth Carlson, Bob S. Carter, Blanca Majem, Clark C. Chen, Emanuele Cocucci, Kirsty Danielson, Amanda Courtright, Saumya Das, Zakaria Y. Abd Elmageed, Daniel Enderle, Alan Ezrin, Marc Ferrer, Jane Freedman, Kahraman Tanriverdi Aug 2015

Meeting Report: Discussions And Preliminary Findings On Extracellular Rna Measurement Methods From Laboratories In The Nih Extracellular Rna Communication Consortium, Louise C. Laurent, Asim B. Abdel-Mageed, P. David Adelson, Jorge Arango, Leonora Balaj, Xandra Breakefield, Elizabeth Carlson, Bob S. Carter, Blanca Majem, Clark C. Chen, Emanuele Cocucci, Kirsty Danielson, Amanda Courtright, Saumya Das, Zakaria Y. Abd Elmageed, Daniel Enderle, Alan Ezrin, Marc Ferrer, Jane Freedman, Kahraman Tanriverdi

Open Access Articles

Extracellular RNAs (exRNAs) have been identified in all tested biofluids and have been associated with a variety of extracellular vesicles, ribonucleoprotein complexes and lipoprotein complexes. Much of the interest in exRNAs lies in the fact that they may serve as signalling molecules between cells, their potential to serve as biomarkers for prediction and diagnosis of disease and the possibility that exRNAs or the extracellular particles that carry them might be used for therapeutic purposes. Among the most significant bottlenecks to progress in this field is the lack of robust and standardized methods for collection and processing of biofluids, separation of ...


The Small Gtpase Rab8 Interacts With Vamp-3 To Regulate The Delivery Of Recycling T-Cell Receptors To The Immune Synapse, Francesca Finetti, Laura Patrussi, Donatella Galgano, Chiara Cassioli, Giuseppe Perinetti, Gregory J. Pazour, Cosima T. Baldari Jul 2015

The Small Gtpase Rab8 Interacts With Vamp-3 To Regulate The Delivery Of Recycling T-Cell Receptors To The Immune Synapse, Francesca Finetti, Laura Patrussi, Donatella Galgano, Chiara Cassioli, Giuseppe Perinetti, Gregory J. Pazour, Cosima T. Baldari

Open Access Articles

IFT20, a component of the intraflagellar transport (IFT) system that controls ciliogenesis, regulates immune synapse assembly in the non-ciliated T-cell by promoting T-cell receptor (TCR) recycling. Here, we have addressed the role of Rab8 (for which there are two isoforms Rab8a and Rab8b), a small GTPase implicated in ciliogenesis, in TCR traffic to the immune synapse. We show that Rab8, which colocalizes with IFT20 in Rab11(+) endosomes, is required for TCR recycling. Interestingly, as opposed to in IFT20-deficient T-cells, TCR(+) endosomes polarized normally beneath the immune synapse membrane in the presence of dominant-negative Rab8, but were unable to undergo the ...


Intraflagellar Transport 27 Is Essential For Hedgehog Signaling But Dispensable For Ciliogenesis During Hair Follicle Morphogenesis, Ning Yang, Li Li, Thibaut Eguether, John P. Sundberg, Gregory J. Pazour, Jiang Chen Jun 2015

Intraflagellar Transport 27 Is Essential For Hedgehog Signaling But Dispensable For Ciliogenesis During Hair Follicle Morphogenesis, Ning Yang, Li Li, Thibaut Eguether, John P. Sundberg, Gregory J. Pazour, Jiang Chen

Open Access Articles

Hair follicle morphogenesis requires precisely controlled reciprocal communications, including hedgehog (Hh) signaling. Activation of the Hh signaling pathway relies on the primary cilium. Disrupting ciliogenesis results in hair follicle morphogenesis defects due to attenuated Hh signaling; however, the loss of cilia makes it impossible to determine whether hair follicle phenotypes in these cilia mutants are caused by the loss of cilia, disruption of Hh signaling, or a combination of these events. In this study, we characterized the function of Ift27, which encodes a subunit of intraflagellar transport (IFT) complex B. Hair follicle morphogenesis of Ift27-null mice was severely impaired, reminiscent ...


Studies Of Oc-Stamp In Osteoclast Fusion: A New Knockout Mouse Model, Rescue Of Cell Fusion, And Transmembrane Topology, Hanna Witwicka, Sung-Yong Hwang, Pablo Reyes-Gutierrez, Hong Jia, Paul E. Odgren, Leah Rae Donahue, Mark J. Birnbaum, Paul R. Odgren Jun 2015

Studies Of Oc-Stamp In Osteoclast Fusion: A New Knockout Mouse Model, Rescue Of Cell Fusion, And Transmembrane Topology, Hanna Witwicka, Sung-Yong Hwang, Pablo Reyes-Gutierrez, Hong Jia, Paul E. Odgren, Leah Rae Donahue, Mark J. Birnbaum, Paul R. Odgren

Open Access Articles

The fusion of monocyte/macrophage lineage cells into fully active, multinucleated, bone resorbing osteoclasts is a complex cell biological phenomenon that utilizes specialized proteins. OC-STAMP, a multi-pass transmembrane protein, has been shown to be required for pre-osteoclast fusion and for optimal bone resorption activity. A previously reported knockout mouse model had only mononuclear osteoclasts with markedly reduced resorption activity in vitro, but with paradoxically normal skeletal micro-CT parameters. To further explore this and related questions, we used mouse ES cells carrying a gene trap allele to generate a second OC-STAMP null mouse strain. Bone histology showed overall normal bone form ...


Nuclear Accessibility Of Beta-Actin Mrna Is Measured By 3d Single-Molecule Real-Time Tracking, Carlas Smith, Stephan Preibisch, Aviva Joseph, Sara Abrahamsson, Bernd Rieger, Eugene Myers, Robert H. Singer, David Grünwald May 2015

Nuclear Accessibility Of Beta-Actin Mrna Is Measured By 3d Single-Molecule Real-Time Tracking, Carlas Smith, Stephan Preibisch, Aviva Joseph, Sara Abrahamsson, Bernd Rieger, Eugene Myers, Robert H. Singer, David Grünwald

Open Access Articles

Imaging single proteins or RNAs allows direct visualization of the inner workings of the cell. Typically, three-dimensional (3D) images are acquired by sequentially capturing a series of 2D sections. The time required to step through the sample often impedes imaging of large numbers of rapidly moving molecules. Here we applied multifocus microscopy (MFM) to instantaneously capture 3D single-molecule real-time images in live cells, visualizing cell nuclei at 10 volumes per second. We developed image analysis techniques to analyze messenger RNA (mRNA) diffusion in the entire volume of the nucleus. Combining MFM with precise registration between fluorescently labeled mRNA, nuclear pore ...


Downregulation Of The Host Gene Jigr1 By Mir-92 Is Essential For Neuroblast Self-Renewal In Drosophila, Yeliz Yuva-Aydemir, Xia-Lian Xu, Ozkan Aydemir, Eduardo Gascon, Serkan Sayin, Wenke Zhou, Yang Hong, Fen-Biao Gao May 2015

Downregulation Of The Host Gene Jigr1 By Mir-92 Is Essential For Neuroblast Self-Renewal In Drosophila, Yeliz Yuva-Aydemir, Xia-Lian Xu, Ozkan Aydemir, Eduardo Gascon, Serkan Sayin, Wenke Zhou, Yang Hong, Fen-Biao Gao

Open Access Articles

Intragenic microRNAs (miRNAs), located mostly in the introns of protein-coding genes, are often co-expressed with their host mRNAs. However, their functional interaction in development is largely unknown. Here we show that in Drosophila, miR-92a and miR-92b are embedded in the intron and 3'UTR of jigr1, respectively, and co-expressed with some jigr1 isoforms. miR-92a and miR-92b are highly expressed in neuroblasts of larval brain where Jigr1 expression is low. Genetic deletion of both miR-92a and miR-92b demonstrates an essential cell-autonomous role for these miRNAs in maintaining neuroblast self-renewal through inhibiting premature differentiation. We also show that miR-92a and miR-92b directly ...


Trafd1 (Fln29) Interacts With Plekhm1 And Regulates Osteoclast Acidification And Resorption, Hanna Witwicka, Hong Jia, Artem B. Kutikov, Pablo Reyes-Gutierrez, Xiang-Dong Li, Paul R. Odgren May 2015

Trafd1 (Fln29) Interacts With Plekhm1 And Regulates Osteoclast Acidification And Resorption, Hanna Witwicka, Hong Jia, Artem B. Kutikov, Pablo Reyes-Gutierrez, Xiang-Dong Li, Paul R. Odgren

Open Access Articles

Plekhm1 is a large, multi-modular, adapter protein implicated in osteoclast vesicle trafficking and bone resorption. In patients, inactivating mutations cause osteopetrosis, and gain-of-function mutations cause osteopenia. Investigations of potential Plekhm1 interaction partners by mass spectrometry identified TRAFD1 (FLN29), a protein previously shown to suppress toll-like receptor signaling in monocytes/macrophages, thereby dampening inflammatory responses to innate immunity. We mapped the binding domains to the TRAFD1 zinc finger (aa 37-60), and to the region of Plekhm1 between its second pleckstrin homology domain and its C1 domain (aa 784-986). RANKL slightly increased TRAFD1 levels, particularly in primary osteoclasts, and the co-localization of ...


Exosomes Derived From Alcohol-Treated Hepatocytes Horizontally Transfer Liver Specific Mirna-122 And Sensitize Monocytes To Lps, Fatemeh Momen-Heravi, Shashi Bala, Karen Kodys, Gyongyi Szabo May 2015

Exosomes Derived From Alcohol-Treated Hepatocytes Horizontally Transfer Liver Specific Mirna-122 And Sensitize Monocytes To Lps, Fatemeh Momen-Heravi, Shashi Bala, Karen Kodys, Gyongyi Szabo

Open Access Articles

Hepatocyte damage and inflammation in monocytes/macrophages are central to the pathogenesis of alcoholic hepatitis (AH). MicroRNAs (miRNAs) regulate all of these processes. MiRNA-122 is abundantly expressed in hepatocytes while monocytes/macrophages have low levels. The role of exosomes in AH and possible cross talk between hepatocyte-derived exosomes and immune cells is not explored yet. Here, we show that the number of exosomes significantly increases in the sera of healthy individuals after alcohol binge drinking and in mice after binge or chronic alcohol consumption. Exosomes isolated from sera after alcohol consumption or from in vitro ethanol-treated hepatocytes contained miRNA-122. Exosomes ...


The P53r172h Mutant Does Not Enhance Hepatocellular Carcinoma Development And Progression, Leanne G. Ahronian, David R. Driscoll, David S. Klimstra, Brian C. Lewis Apr 2015

The P53r172h Mutant Does Not Enhance Hepatocellular Carcinoma Development And Progression, Leanne G. Ahronian, David R. Driscoll, David S. Klimstra, Brian C. Lewis

Open Access Articles

Hepatocellular carcinoma is a highly deadly malignancy, accounting for approximately 800,000 deaths worldwide every year. Mutation of the p53 tumor suppressor gene is a common genetic change in HCC, present in 30% of cases. p53R175H (corresponding to p53R172H in mice) is a hotspot for mutation that demonstrates "prometastatic" gain-of-function in other cancer models. Since the frequency of p53 mutation increases with tumor grade in HCC, we hypothesized that p53R172H is a gain-of-function mutation in HCC that contributes to a decrease in tumor-free survival and an increase in metastasis. In an HCC mouse model, we found that p53R172H/flox mice ...


Genome-Wide Co-Occupancy Of Aml1-Eto And N-Cor Defines The T(8;21) Aml Signature In Leukemic Cells, Daniel J. Trombly, Troy W. Whitfield, Srivatsan Padmanabhan, Jonathan A. R. Gordon, Jane B. Lian, Andre J. Van Wijnen, Kaleem Zaidi, Janet L. Stein, Gary S. Stein Apr 2015

Genome-Wide Co-Occupancy Of Aml1-Eto And N-Cor Defines The T(8;21) Aml Signature In Leukemic Cells, Daniel J. Trombly, Troy W. Whitfield, Srivatsan Padmanabhan, Jonathan A. R. Gordon, Jane B. Lian, Andre J. Van Wijnen, Kaleem Zaidi, Janet L. Stein, Gary S. Stein

Open Access Articles

BACKGROUND: Many leukemias result from chromosomal rearrangements. The t(8;21) chromosomal translocation produces AML1-ETO, an oncogenic fusion protein that compromises the function of AML1, a transcription factor critical for myeloid cell differentiation. Because of the pressing need for new therapies in the treatment of acute myleoid leukemia, we investigated the genome-wide occupancy of AML1-ETO in leukemic cells to discover novel regulatory mechanisms involving AML-ETO bound genes.

RESULTS: We report the co-localization of AML1-ETO with the N-CoR co-repressor to be primarily on genomic regions distal to transcriptional start sites (TSSs). These regions exhibit over-representation of the motif for PU.1 ...


Individual Epigenetic Status Of The Pathogenic D4z4 Macrosatellite Correlates With Disease In Facioscapulohumeral Muscular Dystrophy, Takako I. Jones, Oliver D. King, Charis L. Himeda, Sachiko Homma, Jennifer C. J. Chen, Mary Lou. Beermann, Chi Yan, Charles P. Emerson Jr., Jeffrey B. Miller, Kathryn R. Wagner, Peter L. Jones Mar 2015

Individual Epigenetic Status Of The Pathogenic D4z4 Macrosatellite Correlates With Disease In Facioscapulohumeral Muscular Dystrophy, Takako I. Jones, Oliver D. King, Charis L. Himeda, Sachiko Homma, Jennifer C. J. Chen, Mary Lou. Beermann, Chi Yan, Charles P. Emerson Jr., Jeffrey B. Miller, Kathryn R. Wagner, Peter L. Jones

Open Access Articles

BACKGROUND: Both forms of facioscapulohumeral muscular dystrophy (FSHD) are associated with aberrant epigenetic regulation of the chromosome 4q35 D4Z4 macrosatellite. Chromatin changes due to large deletions of heterochromatin (FSHD1) or mutations in chromatin regulatory proteins (FSHD2) lead to relaxation of epigenetic repression and increased expression of the deleterious double homeobox 4 (DUX4) gene encoded within the distal D4Z4 repeat. However, many individuals with the genetic requirements for FSHD remain asymptomatic throughout their lives. Here we investigated family cohorts of FSHD1 individuals who were either affected (manifesting) or without any discernible weakness (nonmanifesting/asymptomatic) and their unaffected family members to determine ...


Osteopetrorickets Due To Snx10 Deficiency In Mice Results From Both Failed Osteoclast Activity And Loss Of Gastric Acid-Dependent Calcium Absorption, Liang Ye, Leslie R. Morse, Li Zhang, Hajime Sasaki, Jason C. Mills, Paul R. Odgren, Greg Sibbel, James R.L. Stanley, Gee Wong, Ariane Zamarioli, Ricardo A. Battaglino Mar 2015

Osteopetrorickets Due To Snx10 Deficiency In Mice Results From Both Failed Osteoclast Activity And Loss Of Gastric Acid-Dependent Calcium Absorption, Liang Ye, Leslie R. Morse, Li Zhang, Hajime Sasaki, Jason C. Mills, Paul R. Odgren, Greg Sibbel, James R.L. Stanley, Gee Wong, Ariane Zamarioli, Ricardo A. Battaglino

Open Access Articles

Mutations in sorting nexin 10 (Snx10) have recently been found to account for roughly 4% of all human malignant osteopetrosis, some of them fatal. To study the disease pathogenesis, we investigated the expression of Snx10 and created mouse models in which Snx10 was knocked down globally or knocked out in osteoclasts. Endocytosis is severely defective in Snx10-deficient osteoclasts, as is extracellular acidification, ruffled border formation, and bone resorption. We also discovered that Snx10 is highly expressed in stomach epithelium, with mutations leading to high stomach pH and low calcium solubilization. Global Snx10-deficiency in mice results in a combined phenotype: osteopetrosis ...