DOCSLIB.ORG

Sostdc1: a Bmp/Wnt Dual Pathway Antagonist in Breast and Renal Cancers

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Sostdc1: a Bmp/Wnt Dual Pathway Antagonist in Breast and Renal Cancers SOSTDC1: A BMP/WNT DUAL PATHWAY ANTAGONIST IN BREAST AND RENAL CANCERS BY KIMBERLY ROSE BLISH A Dissertation Submitted to the Graduate Faculty of WAKE FOREST UNIVERSITY GRADUATE SCHOOL OF ARTS AND SCIENCES in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Molecular Medicine and Translational Science May 2009 Winston-Salem, North Carolina Approved By: Suzy V. Torti, Ph.D. Advisor ________________________________ Examining Committee: Mark C. Willingham, M.D., Chairman ________________________________ Gregory A. Hawkins, Ph.D. ________________________________ Raymond Penn, Ph.D. ________________________________ William Jeffrey Petty, M.D. ________________________________ ACKNOWLEDGEMENTS At the end of a long research and writing process, I come at last to the part where I can reflect upon the journey with gratitude. However, as I am typing these words last, I am hampered by a diminished vocabulary and I know I shall fall short on the most important words of the document! To all whom I salute below: I sincerely could not have accomplished anything worthwhile without you. These words will not do you justice for your support has meant the world to me. This project would be nonexistent without the opportunities, guidance, and experience offered from my advisor, Suzy Torti and co-advisor, Frank Torti. You both challenged me to become a better scientist. I am indebted to you for giving me and my ideas a “home” for the past 5 years. I am grateful to my committee members (Mark Willingham, Greg Hawkins, Anthony Atala, Ray Penn, Jeff Petty) and many other faculty collaborators who took my ideas seriously, encouraged new directions, and gave of their time and laboratory resources. I have acknowledged specific contributions where appropriate throughout the text. Mark Willingham, Tim Kute, Greg Hawkins, and members of their laboratories were colleagues with indispensible aid and inexhaustible advice. The entire Torti Lab contributed through advice, technical assistance, and at times, “colleague commiseration”. Particular mention goes to Samer Kalakish, ii Matt Triplette, Wei Wang, Seon-Hi Jang, Lan Coffman, Zandra Pinnix, Alice Mims, and Jonathan Storey for their direct contributions to this project. All students rely heavily on laboratory technicians and I was no exception. My thanks especially go to Rong Ma and Julie Brown for keeping the lab running smoothly, yet finding time to teach and answer endless questions. I am particularly indebted to Julie Brown for her hours of support, technical, moral, and spiritual on this project. I would not have arrived at Wake Forest in the first place without a lot of help. I had not considered a PhD degree until the mentoring I received in college from Lowell Hall and Cynthia Davis, both of whom invested in me – not only as one of their students, but as a person. Mark Payne, David Bass, Cash McCall, Jamal Ibdah, Paul Laurienti, Linda McPhail, Bridget Brosnihan, and Kevin High in the Molecular Medicine and MD/PhD programs provided career and administrative support during my transition into and throughout the dual-degree program. I have had the honor of working with an incredibly high caliber of colleagues in the Molecular Medicine, MD/PhD, and Cancer Biology programs and I am proud to be part of these departments. Personally, there was a formidable army of friends and family who would not let me back down and were constantly rooting for me including: • My prayer partners and cheerleaders- may you be abundantly blessed! iii • My extended family at Harvest Point Church, especially the youth group who tried to keep me smiling through it all. • The cancer survivors who shared their stories and their enthusiasm for life: Susan Blish, Kate Hacker, and Bob Smith • The Rose, Pomante, Smith, Blish, LaBarr, and Stotler families for understanding my preoccupation, missed holidays, and late birthday cards and forgiving me when finishing this thesis work became overwhelming. At the end, I couldn’t have made it without the support network that helped sustain me day to day (and provided excellent child care)! • Mom and Dad- There are no better examples of self-sacrificing love and support than you. I am the person I am, having achieved these things- because of you. When the battle was long, you held up my arms. • My husband, Drew. You have put up with everything you promised and more! “Time after Time.” I can’t imagine anyone else I’d rather share this with. I dedicate this work to: Evelyn Smith & Elaine Rose, because I am in awe of all that has been done, Drew, because every day is worth it, and Ethan, because there’s hope for the future. Glory to the One who was, and is, and is to come (Revelations 1:8) iv TABLE OF CONTENTS Page LIST OF ABBREVIATIONS ………………………………………………….. vi LIST OF ILLUSTRATIONS …………………………………………………... xi ABSTRACT…………………………………………………………………….. xiv Chapter I. INTRODUCTION: BMP/WNT PATHWAYS SIGNALING IN CANCER AND SOSTDC1 AS A POTENTIAL DUAL-PATHWAY INHIBITOR……………………………………………………………….. 1 II. THE HUMAN BONE MORPHOGENETIC PROTEIN ANTAGONIST SOSTDC1 IS DOWNREGULATED IN RENAL CANCERS Published in Molecular Biology of the Cell, February 2008…………. 39 III. LOSS OF HETEROZYGOSITY AFFECTING SOSTDC1 IN RENAL TUMORS For Submission to Cancer Epidemiology Biomarkers and Prevention ……………………………………………………………….. 77 IV. SOSTDC1, AN ANTI-PROLIFERATIVE BMP ANTAGONIST, IS POORLY EXPRESSED IN PATIENTS WITH ADVANCED BREAST CANCER In Preparation…………………………………………………………….. 106 V. GENERAL DISCUSSION……………………………………………….. 142 SCHOLASTIC VITA……………………………………………………………. 167 v LIST OF ABBREVIATIONS AHR Aryl Hydrocarbon Receptor AKT Akt/Protein Kinase B Oncogene Family APC Adenomatous Polyposis Coli ALK Activin-Like Kinase AUS Antigen Unmasking Solution BHD Birt-Hogg-Dubé BMP Bone Morphogenetic Protein BMPA BMP Antagonist BMPR BMP Receptor CCN Family of proteins including: CTGF, cyr61, and nov CEU Population of Utah residents with northern or western European ancestry (HapMap designation) CK-1,-2 Casein kinase-1, -2 CTCK C-Terminal Cystine Knot CTGF Connective Tissue Growth Factor Cyr61 Cysteine rich 61 DAN Differential screening-selected gene Aberrative in Neuroblastoma DCIS Ductal Carcinomas In Situ (Breast) DSH/DVL Disheveled DKK Dickkopf vi EGF/R Epidermal Growth Factor/Receptor FBS Fetal Bovine Serum FGF Fibroblast Growth Factor FH Fumerate Hydratase FWT Familial Wilms Tumor locus FRZ Frizzled FSH Follicle Stimulating Hormone GAPDH GlycerAldehyde-3-Phosphate DeHydrogenase GSK-3β Glycogen synthase kinase-3β HapMap International HapMap Project- partnership to database of frequencies of human SNPs hCG human Chorionic Gonadotropin HMEC Human Mammary Epithelial Cell HMER HMECs overexpressing ras oncogene IGF/R Insulin-like Growth Factor/Receptor IHC ImmunoHistoChemistry INT MMTV Integration gene (M. musculus) LCIS Lobular Carcinoma In Situ (Breast) LDLR Low-Density Lipoprotein Receptor LH Luteinizing Hormone LOH Loss-Of-Heterozygosity LRP LDLR Related Protein MAD Mothers against decapentaplegic (D. melanogaster) vii MAPK Mitogen-Activated Protein Kinase MEOX2 MEsenchymal homeobOX-2 MMTV Mouse Mammary Tumor Virus NDP Norrie Disease Protein NGF Nerve Growth Factor Nov Nephroblastoma overexpressed PPAR Peroxisome Proliferator-Activated Receptor PC Pearson’s Coefficient PCP Planar Cell Polarity (Wnt signaling pathway) PI3K PhosphoInositide-3 Kinase P/S Penicillin/Streptomycin PTCH Patched PTEN Phosphatase and TENsin homolog RPTEC Renal Proximal Tubule Epithelial Cells RCC Renal Cell Carcinoma RCC-Clear RCC-Clear Cell Type rh recombinant, human R-Smad Regulatory-Smad RT-CES Real Time-Cell Expansion System® (ACEA Biosciences) sFRP secreted Frizzled-Related Protein SBE Smad Binding Element SDS Sodium Dodecyl Sulfate viii SDS-PAGE SDS-PolyAcrylamide Gel Electrophoresis Smad Mothers against decapentaplegic and SMA family Member (Common name for MAD and SMA homologs) SNP Single Nucleotide Polymorphism SOST SclerOSTin SOSTDC1 SclerOSTin Domain-Containing 1 (H. sapiens) TCF/LEF T-Cell Factor/Lymphoid Enhancing Factor TGF-β Transforming Growth Factor-β TMA Tissue MicroArray Tsg twisted gastrulation UEP UnExtended Primer USAG-1 Uterine Sensitization-Association Gene-1 (R. Norvegius) VHL Von Hippl-Lindau vWF von Willebrand Factor WAGR Wilms tumor, Aniridia, Genitourinary malformation, and mental Retardation syndrome Wg Wingless (D. melanogaster) WIF Wnt Inhibitory Factor WISP Wnt Inducible Signaling Pathway Wnt Wingless-type MMTV integration site family member (Common name for Wg and INT homologs) ix WT Wilms Tumor locus YRU Population of Nigeria residents with Yoruban ancestors (HapMap designation) x LIST OF ILLUSTRATIONS CHAPTER I Figure Page 1. Amino acid composition of SOSTDC1 22 2. CTCK motif in various secreted signaling molecules 25 3. SOSTDC1 alignment with sclerostin 26 CHAPTER II Figure Page 1. Downregulation of Human SOSTDC1 mRNA in 52 Kidney Tumors 2. Immunohistochemical analysis of SOSTDC1 expression In normal kidney and renal cancer subtypes 55 3. Quantification of SOSTDC1 staining 58 4. Normal human SOSTDC1 is secreted and binds to matrix or cell surface proteins around neighboring cells 60 5. rhSOSTDC1 antagonizes the production of phosphorylated Smad in response to BMP-7 signaling 62 6. SOSTDC1 antagonizes Wnt-3a signaling in renal carcinoma cells 64 7. Overexpression of SOSTDC1 suppresses proliferation of 769-P RCC-clear cell cultures 66 Table Page I. Quantitation of SOSTDC1 Immunohistochemistry 56 xi CHAPTER III Figure Page 1. SOSTDC1 Locus 85 2. Genes in 2 Mbp Region of Interest on 7p 86 3. LOH Results
Load more

Recommended publications
  • Evolution of the DAN Gene Family in Vertebrates
    bioRxiv preprint doi: https://doi.org/10.1101/794404; this version posted June 29, 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 4.0 International license. RESEARCH ARTICLE Evolution of the DAN gene family in vertebrates Juan C. Opazo1,2,3, Federico G. Hoffmann4,5, Kattina Zavala1, Scott V. Edwards6 1Instituto de Ciencias Ambientales y Evolutivas, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile. 2David Rockefeller Center for Latin American Studies, Harvard University, Cambridge, MA 02138, USA. 3Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD). 4 Department of Biochemistry, Molecular Biology, Entomology, and Plant Pathology, Mississippi State University, Mississippi State, 39762, USA. Cite as: Opazo JC, Hoffmann FG, 5 Zavala K, Edwards SV (2020) Institute for Genomics, Biocomputing, and Biotechnology, Mississippi State Evolution of the DAN gene family in University, Mississippi State, 39762, USA. vertebrates. bioRxiv, 794404, ver. 3 peer-reviewed and recommended by 6 PCI Evolutionary Biology. doi: Department of Organismic and Evolutionary Biology, Harvard University, 10.1101/794404 Cambridge, MA 02138, USA. This article has been peer-reviewed and recommended by Peer Community in Evolutionary Biology Posted: 29 June 2020 doi: 10.24072/pci.evolbiol.100104 ABSTRACT Recommender: Kateryna Makova The DAN gene family (DAN, Differential screening-selected gene Aberrant in Neuroblastoma) is a group of genes that is expressed during development and plays fundamental roles in limb bud formation and digitation, kidney formation and morphogenesis and left-right axis specification.
    [Show full text]
  • Effects of Chronic Stress on Prefrontal Cortex Transcriptome in Mice Displaying Different Genetic Backgrounds
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Springer - Publisher Connector J Mol Neurosci (2013) 50:33–57 DOI 10.1007/s12031-012-9850-1 Effects of Chronic Stress on Prefrontal Cortex Transcriptome in Mice Displaying Different Genetic Backgrounds Pawel Lisowski & Marek Wieczorek & Joanna Goscik & Grzegorz R. Juszczak & Adrian M. Stankiewicz & Lech Zwierzchowski & Artur H. Swiergiel Received: 14 May 2012 /Accepted: 25 June 2012 /Published online: 27 July 2012 # The Author(s) 2012. This article is published with open access at Springerlink.com Abstract There is increasing evidence that depression signaling pathway (Clic6, Drd1a,andPpp1r1b). LA derives from the impact of environmental pressure on transcriptome affected by CMS was associated with genetically susceptible individuals. We analyzed the genes involved in behavioral response to stimulus effects of chronic mild stress (CMS) on prefrontal cor- (Fcer1g, Rasd2, S100a8, S100a9, Crhr1, Grm5,and tex transcriptome of two strains of mice bred for high Prkcc), immune effector processes (Fcer1g, Mpo,and (HA)and low (LA) swim stress-induced analgesia that Igh-VJ558), diacylglycerol binding (Rasgrp1, Dgke, differ in basal transcriptomic profiles and depression- Dgkg,andPrkcc), and long-term depression (Crhr1, like behaviors. We found that CMS affected 96 and 92 Grm5,andPrkcc) and/or coding elements of dendrites genes in HA and LA mice, respectively. Among genes (Crmp1, Cntnap4,andPrkcc) and myelin proteins with the same expression pattern in both strains after (Gpm6a, Mal,andMog). The results indicate significant CMS, we observed robust upregulation of Ttr gene contribution of genetic background to differences in coding transthyretin involved in amyloidosis, seizures, stress response gene expression in the mouse prefrontal stroke-like episodes, or dementia.
    [Show full text]
  • Transcriptomic and Epigenomic Characterization of the Developing Bat Wing
    ARTICLES OPEN Transcriptomic and epigenomic characterization of the developing bat wing Walter L Eckalbar1,2,9, Stephen A Schlebusch3,9, Mandy K Mason3, Zoe Gill3, Ash V Parker3, Betty M Booker1,2, Sierra Nishizaki1,2, Christiane Muswamba-Nday3, Elizabeth Terhune4,5, Kimberly A Nevonen4, Nadja Makki1,2, Tara Friedrich2,6, Julia E VanderMeer1,2, Katherine S Pollard2,6,7, Lucia Carbone4,8, Jeff D Wall2,7, Nicola Illing3 & Nadav Ahituv1,2 Bats are the only mammals capable of powered flight, but little is known about the genetic determinants that shape their wings. Here we generated a genome for Miniopterus natalensis and performed RNA-seq and ChIP-seq (H3K27ac and H3K27me3) analyses on its developing forelimb and hindlimb autopods at sequential embryonic stages to decipher the molecular events that underlie bat wing development. Over 7,000 genes and several long noncoding RNAs, including Tbx5-as1 and Hottip, were differentially expressed between forelimb and hindlimb, and across different stages. ChIP-seq analysis identified thousands of regions that are differentially modified in forelimb and hindlimb. Comparative genomics found 2,796 bat-accelerated regions within H3K27ac peaks, several of which cluster near limb-associated genes. Pathway analyses highlighted multiple ribosomal proteins and known limb patterning signaling pathways as differentially regulated and implicated increased forelimb mesenchymal condensation in differential growth. In combination, our work outlines multiple genetic components that likely contribute to bat wing formation, providing insights into this morphological innovation. The order Chiroptera, commonly known as bats, is the only group of To characterize the genetic differences that underlie divergence in mammals to have evolved the capability of flight.
    [Show full text]
  • Sostdc1 Plays an Essential Role in Mammalian Tooth Patterning: Tooth Sostdc1 Plays an Essential Role in Mammalian
    Recent Publications in this Series: InsightintotheRodent DentalEvolution Patterning: Tooth anEssentialRoleinMammalian MUNNESostdc1Plays PAULIINA 9/2010 Manu Eeva Plant Secondary Metabolites in Peucedanum palustre and Angelica archangelica and Their Plant Cell Cultures 10/2010 Niina Kivikero Granulation in Miniaturised Fluid Bed Using Electrostatic Atomisation 11/2010 Tiina Heikkilä Miniaturization of Drug Solubility and Dissolution Testings 12/2010 Markus Haapala Heated Nebulizer Microchips for Mass Spectrometry 13/2010 Anu Hynninen Zinc, Cadmium and Lead Resistance Mechanisms in Bacteria and Their Contribution to Biosensing 14/2010 Mart Krupovič Evolutionary Genomics of Prokaryotic Viruses 15/2010 Virginija Cvirkaitė-Krupovič Entry of The Membrane-Containing Bacteriophages into Their Hosts 16/2010 Hanan T. Abbas Hilmi Lactic Acid Bacteria and Their Antimicrobial Peptides: Induction, Detection, Partial Characterization, and Their Potential Applications 17/2010 Tero Viitanen GABAA Receptor Mediated Signalling in the Brain: Inhibition, Shunting and Excitation 18/2010 Giuseppe Balistreri Structure, Function and Intracellular Dynamics of Alphavirus Replication Complexes 19/2010 Kaia Achim Regulation of Gabaergic Neuron Identity and Diversity in The Developing Midbrain Sostdc1 Plays an Essential Role in Mammalian Tooth Patterning: 20/2010 Mari Simola Recovery of Yeast Saccharomyces cerevisiae after Thermal Insult Insight into the Rodent Dental Evolution 21/2010 Kati-Sisko Vellonen Cellular and Computational Methods in Corneal Drug Permeability,
    [Show full text]
  • Investigation of SOSTDC1 Gene in Non-Syndromic Patients with Supernumerary Teeth
    Med Oral Patol Oral Cir Bucal. 2018 Sep 1;23 (5):e531-9. Investigation of SOSTDC1 gene in supernumerary tooth formation Journal section: Oral Medicine and Pathology doi:10.4317/medoral.22520 Publication Types: Research http://dx.doi.org/doi:10.4317/medoral.22520 Investigation of SOSTDC1 gene in non-syndromic patients with supernumerary teeth Volkan Arikan 1, Ozge Cumaogullari 2, Betul-Memis Ozgul 3, Firdevs-Tulga Oz 4 1 DDS, PhD, Assistant Professor, Department of Pediatric Dentistry, Faculty of Dentistry, Kirikkale University, Kirikkale, Turkey 2 PhD, Biotechnology Institute, Ankara University, Ankara, Turkey 3 DDS, PhD, Assistant Professor, Department of Pediatric Dentistry, Faculty of Dentistry, Baskent University, Ankara, Turkey 4 DDS, PhD, Professor, Department of Pediatric Dentistry, Faculty of Dentistry, Ankara University, Ankara, Turkey Correspondence: University of Kirikkale Arikan V, Cumaogullari O, Ozgul BM, Oz FT. Investigation of SOSTDC1 Faculty of Dentistry gene in non-syndromic patients with supernumerary teeth. Med Oral Pa- Department of Pediatric Dentistry tol Oral Cir Bucal. 2018 Sep 1;23 (5):e531-9. 71200-Kirikkale http://www.medicinaoral.com/medoralfree01/v23i5/medoralv23i5p531.pdf Turkey [email protected] Article Number: 22520 http://www.medicinaoral.com/ © Medicina Oral S. L. C.I.F. B 96689336 - pISSN 1698-4447 - eISSN: 1698-6946 eMail: [email protected] Indexed in: Science Citation Index Expanded Received: 13/04/2018 Journal Citation Reports Accepted: 05/07/2018 Index Medicus, MEDLINE, PubMed Scopus, Embase and Emcare Indice Médico Español Abstract Background: The etiology of supernumerary teeth is still unclear however heredity is believed to be a major factor and this idea was supported by several case reports.
    [Show full text]
  • Genome-Scale Analysis of DNA Methylation in Lung Adenocarcinoma and Integration with Mrna Expression
    Downloaded from genome.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Research Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression Suhaida A. Selamat,1 Brian S. Chung,1 Luc Girard,2 Wei Zhang,2 Ying Zhang,3 Mihaela Campan,1 Kimberly D. Siegmund,3 Michael N. Koss,4 Jeffrey A. Hagen,5 Wan L. Lam,6 Stephen Lam,6 Adi F. Gazdar,2 and Ite A. Laird-Offringa1,7 1Department of Surgery, Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90089-9176, USA; 2The Hamon Center for Therapeutic Oncology Research and Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; 3Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90089-9176, USA; 4Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089-9176, USA; 5Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California 90089-9176, USA; 6BC Cancer Research Center, BC Cancer Agency, Vancouver, BC V521L3, Canada Lung cancer is the leading cause of cancer death worldwide, and adenocarcinoma is its most common histological subtype. Clinical and molecular evidence indicates that lung adenocarcinoma is a heterogeneous disease, which has important implications for treatment. Here we performed genome-scale DNA methylation profiling using the Illumina Infinium HumanMethylation27 platform on 59 matched lung adenocarcinoma/non-tumor lung pairs, with genome-scale verifi- cation on an independent set of tissues.
    [Show full text]
  • Sostdc1 a Soluble BMP and Wnt Antagonist That Is Induced by the Interaction Between Myeloma Cells and Osteoblast Lineage Cells
    Bone 122 (2019) 82–92 Contents lists available at ScienceDirect Bone journal homepage: www.elsevier.com/locate/bone Full Length Article Sostdc1: A soluble BMP and Wnt antagonist that is induced by the interaction between myeloma cells and osteoblast lineage cells T ⁎ Z. Faraahia, M. Baud'huinb, P.I. Croucherc, C. Eatond, M.A. Lawsond, a Institute for Cancer Sciences, University of Manchester, UK b INSERM U957, EA 3822, Nantes, France c Bone Biology Division, Garvan Institute of Medical Research, Sydney, Australia d Department of Oncology and Metabolism, Medical School, University of Sheffield, UK ARTICLE INFO ABSTRACT Keywords: Multiple myeloma (MM) is characterised by destructive lytic bone disease, caused by induction of bone re- Sostdc1 sorption and impaired bone formation. Our understanding of the molecular mechanisms responsible for os- Multiple myeloma teoblast suppression, are limited. Using the 5T2MM murine model of MM we have previously shown that Bone morphogenic proteins suppression of the activity of a known inhibitor of bone formation Dikkopf-1 (Dkk1) prevents the development of Wnt lytic bone disease. Here we have demonstrated that another potential inhibitor of bone formation, sclerostin Osteoblastogenesis domain containing 1 (Sostdc1) is expressed at low levels in MM and osteoblast lineage cells when these cells are grown separately in cell culture but its expression is significantly induced in both cell types when these cells are in contact. The distribution of Sostdc1 staining in bones infiltrated with 5TGM1 myeloma cells in vivo suggested its presence in both myeloma and osteoblast lineage populations when in close proximity. We have also shown that recombinant Sostdc1 inhibits both bone morphogenic proteins (BMP2 and 7) and Wnt signalling in primary osteoblasts and suppresses differentiation of these cells.
    [Show full text]
  • Downregulation of Sostdc1 in Testicular Sertoli Cells Is
    www.nature.com/scientificreports OPEN Downregulation of Sostdc1 in Testicular Sertoli Cells is Prerequisite for Onset of Robust Received: 10 October 2018 Accepted: 16 July 2019 Spermatogenesis at Puberty Published: xx xx xxxx Bhola Shankar Pradhan 1, Indrashis Bhattacharya1,2, Rajesh Sarkar1 & Subeer S. Majumdar1,3 An alarming decline in sperm count of men from several countries has become a major concern for the world community. Hormones act on testicular Sertoli cells (Sc) to regulate male fertility by governing the division and diferentiation of germ cells (Gc). However, there is a limited knowledge about Sc specifc gene(s) regulating the spermatogenic output of the testis. Sclerostin domain- containing 1 protein (Sostdc1) is a dual BMP/Wnt regulator is predominantly expressed in the Sc of infant testes which hardly show any sign of spermatogenesis. In order to investigate the role of Sostdc1 in spermatogenic regulation, we have generated transgenic (Tg) rats which induced persistent expression of Sostdc1 in mature Sc causing reduced sperm counts. Although Sc specifc Sostdc1 did not afect the function of either Sc or Leydig cells (Lc) in the adult testis of Tg rat, we observed a selective augmentation of the BMP target genes via activated phospho smad 1/5/8 signaling in Gc leading to apoptosis. Here, for the frst time, we have demonstrated that Sostdc1 is a negative regulator of spermatogenesis, and provided substantial evidence that down regulation of Sostdc1 during puberty is critically essential for quantitatively and qualitatively normal spermatogenesis governing male fertility. About 7% of the world’s male population is infertile, making it a public concern1–4.
    [Show full text]
  • Loss of Heterozygosity and SOSTDC1 in Adult and Pediatric Renal Tumors
    Blish et al. Journal of Experimental & Clinical Cancer Research 2010, 29:147 http://www.jeccr.com/content/29/1/147 RESEARCH Open Access Loss of heterozygosity and SOSTDC1 in adult and pediatric renal tumors Kimberly R Blish1†, Kathryn A Clausen2*†, Gregory A Hawkins3, A Julian Garvin4,5, Mark C Willingham4,5, Julie C Turner2, Frank M Torti2,5, Suzy V Torti5,6 Abstract Background: Deletions within the short arm of chromosome 7 are observed in approximately 25% of adult and 10% of Wilms pediatric renal tumors. Within Wilms tumors, the region of interest has been delineated to a 2-Mb minimal region that includes ten known genes. Two of these ten candidate genes, SOSTDC1 and MEOX2,are particularly relevant to tumor development and maintenance. This finding, coupled with evidence that SOSTDC1 is frequently downregulated in adult renal cancer and regulates both Wingless-Int (Wnt)- and bone morphogenetic protein (BMP)-induced signaling, points to a role for SOSTDC1 as a potential tumor suppressor. Methods: To investigate this hypothesis, we interrogated the Oncomine database to examine the SOSTDC1 levels in adult renal clear cell tumors and pediatric Wilms tumors. We then performed single nucleotide polymorphism (SNP) and sequencing analyses of SOSTDC1 in 25 pediatric and 36 adult renal tumors. Immunohistochemical staining of patient samples was utilized to examine the impact of SOSTDC1 genetic aberrations on SOSTDC1 protein levels and signaling. Results: Within the Oncomine database, we found that SOSTDC1 levels were reduced in adult renal clear cell tumors and pediatric Wilms tumors. Through SNP and sequencing analyses of 25 Wilms tumors, we identified four with loss of heterozygosity (LOH) at 7p and three that affected SOSTDC1.
    [Show full text]
  • Sostdc1 ELISA Kit Mouse (OKEH03125)
    Sostdc1 ELISA Kit Mouse (OKEH03125) Instructions for Use For the quantitative measurement of Sostdc1 in Mouse biological samples. This product is intended for research use only. v1.0 Sostdc1 ELISA Kit (Mouse) (OKEH03125) v1.0 Table of Contents 1. Background ............................................................................................................................................. 2 2. Assay Summary ..................................................................................................................................... 3 3. Storage and Stability .............................................................................................................................. 3 4. Kit Components ...................................................................................................................................... 3 5. Precautions ............................................................................................................................................. 4 6. Required Materials Not Supplied ......................................................................................................... 4 7. Technical Application Tips .................................................................................................................... 4 8. Reagent Preparation .............................................................................................................................. 5 9. Sample Preparation Guidelines ..........................................................................................................
    [Show full text]
  • Population-Specific Genetic Modification of Huntington’S Disease in Venezuela
    RESEARCH ARTICLE Population-specific genetic modification of Huntington's disease in Venezuela Michael J. Chao1,2, Kyung-Hee Kim1,2, Jun Wan Shin1,2, Diane Lucente1,2, Vanessa C. Wheeler1,2, Hong Li3, Jared C. Roach3, Leroy Hood3, Nancy S. Wexler4, Laura B. Jardim5,6, Peter Holmans7, Lesley Jones7, Michael Orth8, Seung Kwak9, Marcy E. MacDonald1,2,10, James F. Gusella1,10,11*, Jong-Min Lee1,2,10* 1 Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America, 2 Department of Neurology, Harvard Medical School, Boston, a1111111111 Massachusetts, United States of America, 3 Institute for Systems Biology, Seattle, Washington, United a1111111111 States of America, 4 Columbia University, New York, New York, United States of America, 5 Departamento a1111111111 de Medicina Interna, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil, 6 ServicËo de GeneÂtica MeÂdica and LaboratoÂrio de IdentificacËão Humana, Hospital de Clinicas de Porto Alegre, Porto Alegre, a1111111111 Brazil, 7 Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of a1111111111 Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom, 8 Department of Neurology, University of Ulm, Ulm, Germany, 9 CHDI Foundation, Princeton, New Jersey, United States of America, 10 Medical and Population Genetics Program, the Broad Institute of M.I.T. and Harvard, Cambridge, Massachusetts, United States of America, 11 Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America OPEN ACCESS * [email protected] (JFG); [email protected] (JML) Citation: Chao MJ, Kim K-H, Shin JW, Lucente D, Wheeler VC, Li H, et al.
    [Show full text]
  • High-Throughput Analysis of WNT Signaling Pathway in Osteoblasts
    UNIVERSITY OF CALIFORNIA, MERCED High-throughput Analysis of WNT Signaling Pathway in Osteoblasts A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Quantitative and Systems Biology by Aimy Sebastian Committee in charge: Dr. Suzanne S. Sindi, Chair Dr. David H. Ardell Dr. Gabriela G. Loots Dr. Jennifer O. Manilay 2016 Copyright Aimy Sebastian, 2016 All rights reserved The Dissertation of Aimy Sebastian is approved, and it is acceptable in quality and form for publication on microfilm and electronically: Gabriela G. Loots Jennifer O. Manilay David H. Ardell Suzanne S. Sindi, Chair Date University of California, Merced 2016 iii Table of Contents Signature Page ..................................................................................................................... iii Table of Contents ................................................................................................................. iv List of Figures ...................................................................................................................... vi List of Tables ..................................................................................................................... viii Acknowledgements .............................................................................................................. ix VITA ..................................................................................................................................... x Abstract .............................................................................................................................
    [Show full text]