DOCSLIB.ORG

A Potential Role for APLP2 in Axogenesis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Potential Role for APLP2 in Axogenesis The Journal of Neuroscience, October 1995, 15(10): 63144326 Distribution of an APP Homolog, APLP2, in the Mouse Olfactory System: A Potential Role for APLP2 in Axogenesis Gopal Thinakaran,1,5 Cheryl A. Kitt, 1,5 A. Jane I. Roskams,” Hilda H. Slunt,1,5 Eliezer Masliah,’ Cornelia von Koch,2,5 Stephen D. Ginsberg,i,5 Gabriele V. Ronnett,‘s4 Randall Ft. Reed,233I6 Donald L. Price,‘,2.4,5 and Sangram S. Sisodiaiz5 ‘Departments of Pathology, 2Neuroscience, 3Molecular Biology and Genetics, and 4Neurology, 5Neuropathology Laboratory, and the 6Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205 and ‘Departments of Neurosciences and Pathology and Neuroscience, University of California at San Diego, La Jolla, California 92093 Deposition of l3-amyloid (AS) in senile plaques is a major APLP2, alternative splicing, chondroitin sulfate glycosami- pathological characteristic of Alzheimer’s disease. Ap is noglycan, glomeruli, olfactory epithelium, o/factory sen- generated by proteolytic processing of amyloici precursor sory neurons] proteins (APP). APP is a member of a family of related poly- peptides that includes amyloid precursor-like proteins A principal pathological feature of Alzheimer’s disease is the APLPl and APLPS. To examine the distribution of APLP2 deposition of Al3 in brain parenchyma (Glenner and Wong, in the nervous system, we generated antibodies specific 1984; Masters et al., 1985). Al3, an -4 kDa polypeptide, is for APLPS and used these reagents in immunocytochemi- derived from larger type I integral membrane glycoproteins, cal and biochemical studies of the rodent nervous system. termed the amyloid precursor proteins (APP) (Kang et al., 1987; In this report, we document that in cortex and hippocam- Kitaguchi et al., 1988; Ponte et al., 1988; Tanzi et al., 1988; pus, APLPS is enriched in postsynaptic compartments. In Golde et al., 1990; K&rig et al., 1992). APP is a member of a the olfactory system, however, APLPS is abundant in ol- family of homologous amyloid precursor-like proteins (APLPs), factory sensory axons, and axon terminals in glomeruli. including APLPl (Wasco et al., 1992) and APLP2 (Sprecher et Confocal microscopy revealed that APLPP is present in al., 1993; Wasco et al., 1993; Slunt et al., 1994). Although the both pre- and postsynaptic compartments in the olfactory members of this gene family share considerable homology in the bulb. Notably, mRNA encoding chondroitin sulfate glycos- amino- and carboxyl-terminal domains, the APLPs differ from aminoglycan (CS GAG)-modified forms of APLPS are en- APP by the absence of the Al3 region. riched in the olfactory epithelium, relative to alternatively- At present, APLP2 is the best characterized member of spliced mRNA, encoding CS GAG-free forms of APLPP. In APLPs. Like APP APLP2 is encoded by several mRNAs de- addition, we demonstrate that CS-modified APLPS forms rived by alternative splicing (Wasco et al., 1993; Sandbrink et accumulate in the olfactory bulb. CS proteoglycans are al., 1994; Slunt et al., 1994). Both APP and APLP2 are ex- known to play an important role in regulating cell migration pressed in brain and peripheral tissues (Wasco et al., 1993; Slunt and neuronal outgrowth. Since sensory neurons in the ol- et al., 1994), and in situ hybridization studies disclose similari- factory epithelium are in a state of continual turnover, ax- ties in the distributions of APP and APLP2 mRNAs in mouse ons of newly generated cells must establish synaptic con- (Slunt et al., 1994) and human (Wasco et al., 1993) CNS. Fi- nections with neurons in the olfactory bulb in adult life. The nally, APLP2 matures through the same unusual secreto- presence of APLPS in olfactory sensory axons and glo- ry/cleavage pathway as APP (Slunt et al., 1994). However, in meruli is consistent with the view that this protein may play contrast to APP-695 and APP-7511770, APLP2-751 is a sub- an important role in axonal pathfinding and/or synaptoge- strate for modification by a single CS GAG chain (Thinakaran nesis. and Sisodia, 1994). [Key words: amyloid precursor-like protein 2, APP, In this study, we report on the distribution of APLP2 in the rodent nervous system using newly generated antibodies specific for APLP2. Consistent with previous in situ hybridization stud- Received Apr. 3, 1995; revised May 22, 1995; accepted May 31, 1995. The CT12 peptide was obtained from the Protein Sequencing and Peptide ies (Slunt et al., 1994), our investigations with the APLPZspe- Synthesis Core maintained by the Center for AIDS Research at Johns Hopkins cific antibodies revealed that APLP2 is expressed in a variety of University School of Medicine under Contract Number 1P30 Al28748 from regions, including cerebral cortex, hippocampus, and thalamus. the National Institute for Allergy and Infectious Diseases of the NIH. We thank Drs. Samuel Gandy, Mike Lee, and Philip Wong for providing antibodies 369, Confocal microscopy revealed prominent colocalization of TuJl, and Myc-I, respectively; Karen Schrader for providing mouse olfactory APLP2 with MAP-2, a postsynaptic marker, in cortex and hip- epithelium RNA; Dr. David Borchelt for providing APP-695 cDNA; and Dr. pocampus. Moreover, APLP2 mRNA is highly expressed in sen- Wilma Wasco for providing the APLPI cDNA. This work was supported by grants from the NIA, NINDS, American Health Assistance Foundation, Al- sory neurons in the olfactory epithelium, and the encoded poly- zheimer’s Association, and the Adler Foundation. peptide is abundant in olfactory sensory axons, and axon ter- Corresoondence should be addressed to Dr. Sanaram S. Sisodia. The Johns Hopkins University School of Medicine, Neuropathilogy Laboratory, 558 Ross minals in glomeruli. In contrast to its predominant postsynaptic Research Building, 720 Rutland Avenue, Baltimore, MD 21205-2196. localization in neurons in cortex and hippocampus, APLP2 is Copyright 0 1995 Society for Neuroscience 0270-6474/95/156314-13$05.00/O present in both pre- and postsynaptic compartments in the ol- The Journal of Neuroscience, October 1995, 75(10) 6315 factory bulb. Notably, mRNA encoding CS GAG-modified cells,an African greenmonkey kidney line, weretransiently transfected forms of APLP2 are highly represented in the olfactory epithe- in 60 mm plates with 10 pg of CsCl-purified plasmid DNA using a high-efficiency calcium phosphate method (Chen and Okayama, 1987). hum, and CS GAG modified forms of APLP2 accumulate in the Thirty-six hours after transfection, cells were labeled with 200 l&i/ml olfactory bulb. Since olfactory sensory neurons are continually 35S-methionine (Du Pont NEN, Wilmington, DE) for 3 hr in Dulbecco’s turned over, axons of newly generated neurons must establish modified Eagle medium lacking methionine and supplemented with 1% synaptic connections with neurons in the olfactory bulb in adult dialyzed fetal calf serum. Detergent lysates and conditioned medium prepared from labeled cells were subject to immunoprecipitation anal- life. Taken together with the view that CS proteoglycans play isis as described (Sisodia et al., 1996; Slunt et al., 1994):CT12, D2-I, an important role in regulating cell migration and neuronal out- and D2-II antibodies were used at 1:2500 dilution for Western blot growth (for review, see Wight et al., 1992), the unique localiza- analysis of lysates prepared from cells transiently expressing APP, tion of APLP2 in olfactory sensory axons and glomemli is con- APLPl, or APLP2. sistent with the notion that this protein may play an important In situ hybridization. Sequences that encode residues 568-681 of mouse APLP2 were cloned into Bluescript KS+ (Slunt et al., 1994) and role in axonal pathfinding and/or synaptogenesis. used as templates to generate sense or antisense 33P-labeled riboprobes using a RNA transcription kit (Stratagene, La Jolla, CA). Sections (10 Materials and Methods pm) cut from fixed frozen mouse nasal epithelium were dried onto slides coated with Fol’s mounting medium, fixed in 4% paraformalde- Antibodies. Ab369 is a polyclonalantibody raised against the entire hyde (PFA) for 20 min and rinsed in phosphate-buffered saline (PBS) cytoplasmic domain (residues 645-694) of APP-695 (Buxbaum et al., and deionized water. After acetylation in 0.25% acetic anhydride pre- 1990), and was kindly provided by Dr. Samuel Gandy (Cornell Uni- pared in 0.1 M triethanolamine, sections were rinsed in PBS and de- versity Medical College, New York). c-Myc-modified APLP2 polypep- hydrated through a graded series of alcohol, and then dried. Sections tides (Thinakaran and Sisodia, 1994) were immunoprecipitated using were hybridized overnight at 55°C in a buffer containing 50% formam- polyclonal antiserum Myc-I (provided by Dr. Philip Wong, Department ide, 10% dextran sulfate, 0.3 M NaCl, 20 mu Tris (pH 7.5), 10 mu of Pathology, The Johns Hopkins University School of Medicine, Bal- Dm, 5 mu EDTA, 1 X Denhardt’s solution and 0.4 mg/ml yeast tRNA, timore), raised against the synthetic peptide MEQKLISEEDLN (Lee et X al., 1993). and 1 rig/slideof labeledprobe (-2 lo6 cpm/ng).Slides were washed asfollows: 5 X SSC (1 X SSC = 0.15 M NaCl, 0.015 M sodium citrate) To generate polyclonal APLP2-specific antibody CT12, a synthetic X peptide corresponding to the C-terminal 12 amino acids (residues 740- and 1 mu D’IT at 55°Cfor 20 min; 50% formamide,2 SSC and 1 mu D’lT at 60°C for 30 min; 10 mu Tiis (pH 7.5), 0.5 M NaCl, and 5 75 1) of mouse APLP2-75 1 with an additional cysteine at the N-terminus mu EDTA (TNE buffer) at 37°C three times 10 min each; TNE buffer (CNPTYKYLEQMQI) was coupled to maleimide-activated keyhole containing 20 kg/ml RNase A at 37°C for 45 min; TNE buffer at 37°C limpet hemocyanin (Imject, Pierce Chemical Co., Rockford, IL). The for 15 min: 50% formamide.
Load more

Recommended publications
  • Using Evolutionary Conserved Modules in Gene Networks As a Strategy to Leverage High Throughput Gene Expression Queries Jeanne M
    Ecology, Evolution and Organismal Biology Ecology, Evolution and Organismal Biology Publications 9-2010 Using Evolutionary Conserved Modules in Gene Networks as a Strategy to Leverage High Throughput Gene Expression Queries Jeanne M. Serb Iowa State University, [email protected] Megan C. Orr Iowa State University M. Heather West Greenlee Iowa State University, [email protected] Follow this and additional works at: http://lib.dr.iastate.edu/eeob_ag_pubs Part of the Ecology and Evolutionary Biology Commons, Genetics Commons, and the Systems Biology Commons The ompc lete bibliographic information for this item can be found at http://lib.dr.iastate.edu/ eeob_ag_pubs/19. For information on how to cite this item, please visit http://lib.dr.iastate.edu/ howtocite.html. This Article is brought to you for free and open access by the Ecology, Evolution and Organismal Biology at Iowa State University Digital Repository. It has been accepted for inclusion in Ecology, Evolution and Organismal Biology Publications by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Using Evolutionary Conserved Modules in Gene Networks as a Strategy to Leverage High Throughput Gene Expression Queries Abstract Background: Large-scale gene expression studies have not yielded the expected insight into genetic networks that control complex processes. These anticipated discoveries have been limited not by technology, but by a lack of effective strategies to investigate the data in a manageable and meaningful way. Previous work suggests that using a pre-determined seednetwork of gene relationships to query large-scale expression datasets is an effective way to generate candidate genes for further study and network expansion or enrichment.
    [Show full text]
  • APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans
    Tkatchenko, A. V., Tkatchenko, T. V., Guggenheim, J. A., Verhoeven, V. J. M., Hysi, P. G., Wojciechowski, R., Singh, P. K., Kumar, A., Thinakaran, G., Williams, C. (2015). APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans. PLoS Genetics, 11(8), [e1005432]. https://doi.org/10.1371/journal.pgen.1005432 Publisher's PDF, also known as Version of record License (if available): CC BY Link to published version (if available): 10.1371/journal.pgen.1005432 Link to publication record in Explore Bristol Research PDF-document This is the final published version of the article (version of record). It first appeared online via Public Library of Science at http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1005432. Please refer to any applicable terms of use of the publisher. University of Bristol - Explore Bristol Research General rights This document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/red/research-policy/pure/user-guides/ebr-terms/ RESEARCH ARTICLE APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans Andrei V. Tkatchenko1,2☯*, Tatiana V. Tkatchenko1☯, Jeremy A. Guggenheim3☯, Virginie J. M. Verhoeven4,5, Pirro G. Hysi6, Robert Wojciechowski7,8, Pawan Kumar Singh9, Ashok Kumar9,10, Gopal Thinakaran11, Consortium for Refractive Error and Myopia (CREAM)¶, Cathy Williams12 1 Department of Ophthalmology, Columbia University, New York, New York, United
    [Show full text]
  • APLP2 Regulates Neuronal Stem Cell Differentiation During Cortical
    1268 Research Article APLP2 regulates neuronal stem cell differentiation during cortical development S. Ali M. Shariati1,2, Pierre Lau1,2, Bassem A. Hassan1,2, Ulrike Mu¨ ller3, Carlos G. Dotti1,2,4,*, Bart De Strooper1,2,* and Annette Ga¨rtner1,2,* 1KU Leuven, Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), 3000 Leuven, Belgium 2VIB Center for the Biology of Disease, 3000 Leuven, Belgium 3Institute of Pharmacy and Molecular Biotechnology, University Heidelberg, 69120 Heidelberg, Germany 4Centro de Biologı´a Molecular Severo Ochoa, CSIC/UAM, C/Nicola´s Cabrera 1, Campus de la Universidad Auto´noma de Madrid, 28049 Madrid, Spain *Authors for correspondence ([email protected]; [email protected]; [email protected]) Accepted 14 December 2012 Journal of Cell Science 126, 1268–1277 ß 2013. Published by The Company of Biologists Ltd doi: 10.1242/jcs.122440 Summary Expression of amyloid precursor protein (APP) and its two paralogues, APLP1 and APLP2 during brain development coincides with key cellular events such as neuronal differentiation and migration. However, genetic knockout and shRNA studies have led to contradictory conclusions about their role during embryonic brain development. To address this issue, we analysed in depth the role of APLP2 during neurogenesis by silencing APLP2 in vivo in an APP/APLP1 double knockout mouse background. We find that under these conditions cortical progenitors remain in their undifferentiated state much longer, displaying a higher number of mitotic cells. In addition, we show that neuron-specific APLP2 downregulation does not impact the speed or position of migrating excitatory cortical neurons.
    [Show full text]
  • Amyloid Precursor Protein and Amyloid Precursor-Like Protein 2 in Cancer
    www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 15 Amyloid precursor protein and amyloid precursor-like protein 2 in cancer Poomy Pandey1, Bailee Sliker1, Haley L. Peters1,6, Amit Tuli1,2,7, Jonathan Herskovitz1, Kaitlin Smits1, Abhilasha Purohit3, Rakesh K. Singh3,4, Jixin Dong1,4, Surinder K. Batra2,4, Donald W. Coulter4,5 and Joyce C. Solheim1,2,3,4 1 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA 2 Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA 3 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA 4 Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA 5 Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, USA 6 Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA 7 Wellcome Trust/DBT India Alliance Intermediate Fellow, CSIR-Institute of Microbial Technology, Chandigarh, India Correspondence to: Joyce C. Solheim, email: [email protected] Keywords: amyloid precursor protein, amyloid precursor-like protein 2, cancer, growth, migration Received: October 02, 2015 Accepted: January 23, 2016 Published: January 31, 2016 ABSTRACT Amyloid precursor protein (APP) and its family members amyloid precursor- like protein 1 (APLP1) and amyloid precursor-like protein 2 (APLP2) are type 1 transmembrane glycoproteins that are highly conserved across species. The transcriptional regulation of APP and APLP2 is similar but not identical, and the cleavage of both proteins is regulated by phosphorylation. APP has been implicated in Alzheimer’s disease causation, and in addition to its importance in neurology, APP is deregulated in cancer cells.
    [Show full text]
  • The Human Β-Amyloid Precursor Protein: Biomolecular and Epigenetic Aspects
    BioMol Concepts 2015; 6(1): 11–32 Review Khue Vu Nguyen* The human β-amyloid precursor protein: biomolecular and epigenetic aspects Abstract: Beta-amyloid precursor protein (APP) is a mem- SAD in particular. Accurate quantification of various APP- brane-spanning protein with a large extracellular domain mRNA isoforms in brain tissues is needed, and antisense and a much smaller intracellular domain. APP plays a drugs are potential treatments. central role in Alzheimer’s disease (AD) pathogenesis: APP processing generates β-amyloid (Aβ) peptides, which Keywords: Alzheimer’s disease; autism; β-amyloid pre- are deposited as amyloid plaques in the brains of AD cursor protein; β-amyloid (Aβ) peptide; epigenetics; individuals; point mutations and duplications of APP are epistasis; fragile X syndrome; genomic rearrangenments; causal for a subset of early-onset familial AD (FAD) (onset HGprt; Lesch-Nyhan syndrome. age < 65 years old). However, these mutations in FAD rep- ∼ resent a very small percentage of cases ( 1%). Approxi- DOI 10.1515/bmc-2014-0041 mately 99% of AD cases are nonfamilial and late-onset, Received December 10, 2014; accepted January 22, 2015 i.e., sporadic AD (SAD) (onset age > 65 years old), and the pathophysiology of this disorder is not yet fully under- stood. APP is an extremely complex molecule that may be functionally important in its full-length configuration, as well as the source of numerous fragments with vary- Introduction ing effects on neural function, yet the normal function of The β-amyloid precursor protein (APP) belongs to a APP remains largely unknown. This article provides an family of evolutionary and structurally related proteins.
    [Show full text]
  • Building the Vertebrate Codex Using the Gene Breaking Protein Trap Library
    TOOLS AND RESOURCES Building the vertebrate codex using the gene breaking protein trap library Noriko Ichino1, MaKayla R Serres1, Rhianna M Urban1, Mark D Urban1, Anthony J Treichel1, Kyle J Schaefbauer1, Lauren E Greif1, Gaurav K Varshney2,3, Kimberly J Skuster1, Melissa S McNulty1, Camden L Daby1, Ying Wang4, Hsin-kai Liao4, Suzan El-Rass5, Yonghe Ding1,6, Weibin Liu1,6, Jennifer L Anderson7, Mark D Wishman1, Ankit Sabharwal1, Lisa A Schimmenti1,8,9, Sridhar Sivasubbu10, Darius Balciunas11, Matthias Hammerschmidt12, Steven Arthur Farber7, Xiao-Yan Wen5, Xiaolei Xu1,6, Maura McGrail4, Jeffrey J Essner4, Shawn M Burgess2, Karl J Clark1*, Stephen C Ekker1* 1Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States; 2Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, United States; 3Functional & Chemical Genomics Program, Oklahoma Medical Research Foundation, Oklahoma City, United States; 4Department of Genetics, Development and Cell Biology, Iowa State University, Ames, United States; 5Zebrafish Centre for Advanced Drug Discovery & Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Unity Health Toronto & University of Toronto, Toronto, Canada; 6Department of Cardiovascular Medicine, Mayo Clinic, Rochester, United States; 7Department of Embryology, Carnegie Institution for Science, Baltimore, United States; 8Department of Clinical Genomics, Mayo Clinic, Rochester, United States; 9Department of Otorhinolaryngology, Mayo Clinic, Rochester, United States; 10Genomics and Molecular Medicine Unit, CSIR– 11 *For correspondence: Institute of Genomics and Integrative Biology, Delhi, India; Department of [email protected] (KJC); Biology, Temple University, Philadelphia, United States; 12Institute of Zoology, [email protected] (SCE) Developmental Biology Unit, University of Cologne, Cologne, Germany Competing interests: The authors declare that no competing interests exist.
    [Show full text]
  • Keratinocytes from APP/APLP2-Deficient Mice Are Impaired in Proliferation, Adhesion and Migration in Vitro
    EXPERIMENTAL CELL RESEARCH 312 (2006) 1939– 1949 available at www.sciencedirect.com www.elsevier.com/locate/yexcr Research Article Keratinocytes from APP/APLP2-deficient mice are impaired in proliferation, adhesion and migration in vitro Christina Siemesa,1, Thomas Quasta,2, Christiane Kummera,3, Sven Wehnera,4, Gregor Kirfela, Ulrike Müllerb, Volker Herzoga,⁎ aInstitute of Cell Biology and Bonner Forum Biomedizin, University of Bonn, Ulrich-Haberlandstr. 61A, 53121 Bonn, Germany bMax Planck Institute for Brain Research, Deutschordenstr. 46, 60528 Frankfurt, Germany and Institute for Pharmacy and Molecular Biotechnology, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany ARTICLE INFORMATION ABSTRACT Article Chronology: Growing evidence shows that the soluble N-terminal form (sAPPα) of the amyloid precursor Received 4 January 2006 protein (APP) represents an epidermal growth factor fostering keratinocyte proliferation, Revised version received migration and adhesion. APP is a member of a protein family including the two mammalian 22 February 2006 amyloid precursor-like proteins APLP1 and APLP2. In the mammalian epidermis, only APP Accepted 23 February 2006 and APLP2 are expressed. APP and APLP2-deficient mice die shortly after birth but do not Available online 11 April 2006 display a specific epidermal phenotype. In this report, we investigated the epidermis of APP and/or APLP2 knockout mice. Basal keratinocytes showed reduced proliferation in vivo by Abbreviations: about 40%. Likewise, isolated keratinocytes exhibited reduced proliferation rates in vitro, APP, β-amyloid precursor protein which could be completely rescued by either exogenously added recombinant sAPPα,orby APLP1, β-amyloid precursor co-culture with dermal fibroblasts derived from APP knockout mice. Moreover, APP- like protein 1 knockout keratinocytes revealed reduced migration velocity resulting from severely APLP2, β-amyloid precursor compromised cell substrate adhesion.
    [Show full text]
  • Extracting Unrecognized Gene Relationships from the Biomedical Literature Via Matrix Factorizations
    Extracting Unrecognized Gene Relationships from the Biomedical Literature via Matrix Factorizations Hyunsoo Kim∗1, Haesun Park∗1 and Barry L. Drake1 1 College of Computing, Georgia Institute of Technology, 266 Ferst Drive, Atlanta, GA 30332, USA. Email: H. Kim∗- [email protected]; H. Park∗- [email protected]; B. L. Drake - [email protected]; ∗Corresponding author Abstract Background: The construction of literature-based networks of gene-gene interactions is one of the most important applications of text mining in bioinformatics. Extracting potential gene relationships from the biomedical literature may be helpful in building biological hypotheses that can be explored further experimentally. Recently, latent semantic indexing based on the singular value decomposition (LSI/SVD) has been applied to gene retrieval. However, the determination of the number of factors k used in the reduced rank matrix is still an open problem. Results: In this paper, we introduce a way to incorporate a priori knowledge of gene relationships into LSI/SVD to determine the number of factors. We also explore the utility of the non-negative matrix factorization (NMF) to extract unrecognized gene relationships from the biomedical literature by taking advantage of known gene relationships. A gene retrieval method based on NMF (GR/NMF) showed comparable performance with LSI/SVD. Conclusions: Using known gene relationships of a given gene, we can determine the number of factors used in the reduced rank matrix and retrieve unrecognized genes related with the given gene by LSI/SVD or GR/NMF. 1 Background Latent semantic indexing based on the singular value decomposition (LSI/SVD) [1, 2] uses the truncated singular value decomposition as a low-rank approximation of a term-by-document matrix.
    [Show full text]
  • APP Binds to the EGFR Ligands HB-EGF and EGF, Acting Synergistically with EGF to Promote ERK Signaling and Neuritogenesis
    bioRxiv preprint doi: https://doi.org/10.1101/2020.06.12.149062; this version posted June 13, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. APP binds to the EGFR ligands HB-EGF and EGF, acting synergistically with EGF to promote ERK signaling and neuritogenesis Joana F. da Rocha1, Luísa Bastos1,#, Sara C. Domingues1, Ana R. Bento1, Uwe Konietzko2, Odete A. B. da Cruz e Silva1,*, Sandra I. Vieira1,* 1Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, Agra do Crasto, 3810-193 Aveiro, Portugal. 2Institute for Regenerative Medicine (IREM), University of Zurich, Zurich, Switzerland #Currently at Roche Sistemas de Diagnósticos, Lda, 2720-413 Amadora, Portugal *equally contributing authors Corresponding Author: Sandra I. Vieira E-mail address: [email protected] Phone: +351 234 247 256 Institute of Biomedicine (iBiMED) Department of Medical Sciences University of Aveiro Agra do Castro 3810-193 Aveiro, Portugal bioRxiv preprint doi: https://doi.org/10.1101/2020.06.12.149062; this version posted June 13, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract The amyloid precursor protein (APP) is a transmembrane glycoprotein central to Alzheimer's disease (AD) with functions in brain development and plasticity, including in neurogenesis and neurite outgrowth.
    [Show full text]
  • Redundancy and Divergence in the Amyloid Precursor Protein Family ⇑ S
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS Letters 587 (2013) 2036–2045 journal homepage: www.FEBSLetters.org Review Redundancy and divergence in the amyloid precursor protein family ⇑ S. Ali M. Shariati, Bart De Strooper KU Leuven, Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), 3000 Leuven, Belgium VIB Center for the Biology of Disease, 3000 Leuven, Belgium article info abstract Article history: Gene duplication provides genetic material required for functional diversification. An interesting Received 8 May 2013 example is the amyloid precursor protein (APP) protein family. The APP gene family has experienced Accepted 8 May 2013 both expansion and contraction during evolution. The three mammalian members have been stud- Available online 23 May 2013 ied quite extensively in combined knock out models. The underlying assumption is that APP, amy- loid precursor like protein 1 and 2 (APLP1, APLP2) are functionally redundant. This assumption is Edited by Alexander Gabibov, Vladimir Skulachev, Felix Wieland and Wilhelm Just primarily supported by the similarities in biochemical processing of APP and APLPs and on the fact that the different APP genes appear to genetically interact at the level of the phenotype in combined knockout mice. However, unique features in each member of the APP family possibly contribute to Keywords: Amyloid precursor protein specification of their function. In the current review, we discuss the evolution and the biology of the Amyloid like precursor protein APP protein family with special attention to the distinct properties of each homologue. We propose Evolution that the functions of APP, APLP1 and APLP2 have diverged after duplication to contribute distinctly Cortex to different neuronal events.
    [Show full text]
  • AЯPP/APLP2 Family of Kunitz Serine Proteinase Inhibitors Regulate
    5666 • The Journal of Neuroscience, April 29, 2009 • 29(17):5666–5670 Brief Communications A␤PP/APLP2 Family of Kunitz Serine Proteinase Inhibitors Regulate Cerebral Thrombosis Feng Xu,1 Mary Lou Previti,1 Marvin T. Nieman,2 Judianne Davis,1 Alvin H. Schmaier,2 and William E. Van Nostrand1 1Department of Medicine, Stony Brook University, Stony Brook, New York 11794-8153, and 2Department of Medicine, Division of Hematology/Oncology, Case Western Reserve University, Cleveland, Ohio 44106 The amyloid ␤-protein precursor (A␤PP) is best recognized as the precursor to the A␤ peptide that accumulates in the brains of patients with Alzheimer’s disease, but less is known about its physiological functions. Isoforms of A␤PP that contain a Kunitz-type serine proteinase inhibitor (KPI) domain are expressed in brain and, outside the CNS, in circulating blood platelets. Recently, we showed that KPI-containing forms of A␤PP regulates cerebral thrombosis in vivo (Xu et al., 2005, 2007). Amyloid precursor like protein-2 (APLP2), a closelyrelatedhomologtoA␤PP,alsopossessesahighlyconservedKPIdomain.Virtuallynothingisknownofitsfunction.Here,weshow that APLP2 also regulates cerebral thrombosis risk. Recombinant purified KPI domains of A␤PP and APLP2 both inhibit the plasma Ϫ Ϫ Ϫ Ϫ clotting in vitro. In a carotid artery thrombosis model, both A␤PP / and APLP2 / mice exhibit similar significantly shorter times to vessel occlusion compared with wild-type mice indicating a prothrombotic phenotype. Similarly, in an experimental model of intrace- rebral hemorrhage, both A␤PP Ϫ/Ϫ and APLP2 Ϫ/Ϫ mice produce significantly smaller hematomas with reduced brain hemoglobin content compared with wild-type mice. Together, these results indicate that A␤PP and APLP2 share overlapping anticoagulant functions with regard to regulating thrombosis after cerebral vascular injury.
    [Show full text]
  • Amyloid Precursor Protein Interaction Network in Human Testis
    Silva et al. BMC Bioinformatics (2015) 16:12 DOI 10.1186/s12859-014-0432-9 RESEARCH ARTICLE Open Access Amyloid precursor protein interaction network in human testis: sentinel proteins for male reproduction Joana Vieira Silva1†, Sooyeon Yoon2†, Sara Domingues3, Sofia Guimarães3, Alexander V Goltsev2, Edgar Figueiredo da Cruz e Silva1ˆ, José Fernando F Mendes2, Odete Abreu Beirão da Cruz e Silva3 and Margarida Fardilha1,4* Abstract Background: Amyloid precursor protein (APP) is widely recognized for playing a central role in Alzheimer's disease pathogenesis. Although APP is expressed in several tissues outside the human central nervous system, the functions of APP and its family members in other tissues are still poorly understood. APP is involved in several biological functions which might be potentially important for male fertility, such as cell adhesion, cell motility, signaling, and apoptosis. Furthermore, APP superfamily members are known to be associated with fertility. Knowledge on the protein networks of APP in human testis and spermatozoa will shed light on the function of APP in the male reproductive system. Results: We performed a Yeast Two-Hybrid screen and a database search to study the interaction network of APP in human testis and sperm. To gain insights into the role of APP superfamily members in fertility, the study was extended to APP-like protein 2 (APLP2). We analyzed several topological properties of the APP interaction network and the biological and physiological properties of the proteins in the APP interaction network were also specified by gene ontologyand pathways analyses. We classified significant features related to the human male reproduction for the APP interacting proteins and identified modules of proteins with similar functional roles which may show cooperative behavior for male fertility.
    [Show full text]