DOCSLIB.ORG

Effect of JAK-STAT Pathway in Regulation of Fatty Liver Hemorrhagic Syndrome in Chickens

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Effect of JAK-STAT Pathway in Regulation of Fatty Liver Hemorrhagic Syndrome in Chickens Open Access Anim Biosci Vol. 34, No. 1:143-153 January 2021 https://doi.org/10.5713/ajas.19.0874 pISSN 2765-0189 eISSN 2765-0235 Effect of JAK-STAT pathway in regulation of fatty liver hemorrhagic syndrome in chickens Yaling Zhu1,2,3,a, Huirong Mao1,a, Gang Peng1, Qingjie Zeng1, Qing Wei1, Jiming Ruan1,*, and Jianzhen Huang1,* * Corresponding Authors: Objective: To explore the molecular mechanisms of fatty liver hemorrhagic syndrome (FLHS) Jiming Ruan Tel: +86-791-83813080, Fax: +86-791-83900189, in laying hens, an experiment was conducted to reveal the differences in histopathological E-mail: [email protected] observation and gene expression between FLHS group and normal group. Jianzhen Huang Methods: We compared the histopathological difference using hematoxylin and eosin Tel: +86-791-83813080, Fax: +86-791-83900189, E-mail: [email protected] staining and proceeded with RNA sequencing of adipose tissue to search differentially expressed genes and enriched biological processes and pathways. Then we validated the 1 College of Animal Science and Technology, mRNA expression levels by real-time polymerase chain reaction and quantified protein Jiangxi Agricultural University, Nanchang, 330045, China levels in the circulation by enzyme-linked immunosorbent assay. 2 Department of Pathophysiology, Anhui Results: We identified 100 differentially expressed transcripts corresponding to 66 genes Medical University, Hefei 230000, China (DEGs) were identified between FLHS-affected group and normal group. Seven DEGs were 3 Laboratory Animal Research Center, College of Basic Medical Science, Anhui Medical significantly enriched in the immune response process and lipid metabolic process, including University, Hefei 230000, China phospholipase A2 group V, WAP kunitz and netrin domain containing 2, delta 4-desaturase sphingolipid 2, perilipin 3, interleukin-6 (IL-6), ciliary neurotrophic factor (CNTF), and a These authors contributed equally to this suppressor of cytokine signaling 3 (SOCS3). And these genes could be the targets of immune work. response and be involved in metabolic homeostasis during the process of FLHS in laying ORCID hens. Based on functional categories of the DEGs, we further proposed a model to explain Yaling Zhu the etiology and pathogenesis of FLHS. IL-6 and SOCS3 mediate inflammatory responses https://orcid.org/0000-0001-8544-1507 Huirong Mao and the satiety hormone of leptin, induce dysfunction of Jak-STAT signaling pathway, leading https://orcid.org/0000-0003-2588-1521 to insulin resistance and lipid metabolic disorders. Conversely, CNTF may reduce tissue Gang Peng destruction during inflammatory attacks and confer protection from inflammation-induced https://orcid.org/0000-0002-5881-7297 Qingjie Zeng insulin resistance in FLHS chickens. https://orcid.org/0000-0001-7739-6793 Conclusion: These findings highlight the therapeutic implications of targeting the JAK- Qing Wei STAT pathway. Inhibition of IL6 and SOCS3 and facilitation of CNTF could serve as a https://orcid.org/0000-0002-9198-7378 Jiming Ruan favorable strategy to enhance insulin action and improve glucose homoeostasis, which are https://orcid.org/0000-0002-2387-1525 of importance for treating obesity-related disorders for chickens. Jianzhen Huang https://orcid.org/0000-0001-8086-1860 Keywords: Fatty Liver Hemorrhagic Syndrome; RNA-Seq; JAK-STAT Pathway; Differentially Submitted Nov 12, 2019; Revised Jan 13, 2020; Expressed Genes; Chicken Accepted Feb 10, 2020 INTRODUCTION Fatty liver hemorrhagic syndrome (FLHS) is a lipid metabolism disorder, which is mostly observed in commercial laying hens. FLHS causes a dramatic drop in egg production, even leads to an increase in mortality and results in considerable economic losses in the poultry industry [1]. For FLHS affected hens, the most obvious changes are enlarged and yellowish, putty-colored livers with various degrees of hemorrhages and an excessive amount of ab- dominal fat. Several factors have been implicated in the cause of FLHS, including nutrition, environment, heredity, toxic substances and hormones [2,3]. The major cause of FLHS is nutrition, as 97% of the affected birds were found to have large fat depots or were obese [4]. In modern poultry industry, an excessive intake of dietary energy is the major cause Copyright © 2021 by Animal Bioscience This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, www.animbiosci.org and reproduction in any medium, provided the original work is properly cited. 143 Zhu et al (2021) Anim Biosci 34:143-153 of FLHS. Recently, a high-energy low-protein (HELP) diet (Approval number: JXAULL-20190019). induced FLHS model has been successfully established [5]. The metabolic disorders such as obesity and liver steatosis Experimental animals and tissue collection often result from the disruption of lipid homeostasis and over- All animal experiments were approved by the Jiangxi Agri- activation of immune pathways. And these damages are cultural University Animal Care and Use Committee. Ninety commonly localized around expanding volumes of adipose healthy 155-day-old Hyline Brown layers with an average tissue, and in particular visceral adipose tissue [6]. Adipose body weight of 1.5 kg were chosen in this study. All layers tissue is an important endocrine organ that controls energy were acclimatized for 7 days before the start of the experiment. hemostasis by storing excess energy in the form of triacylg- These layers were randomly divided into the experimental lycerol (TAG) and releasing energy in the form of free fatty and control groups, and each group contained 45 layers with acid. Excessive lipid storage in adipose tissue results in obe- 3 replicates. These chickens were fed the same basal diet that sity and ultimately its related complications including insulin was formulated to meet the nutritional requirements of layers resistance, non-alcoholic fatty liver disease and other lipid [11]. Layers in the control group were fed basal diet, and metabolic diseases [7]. Alternatively, adipose tissue is cur- layers in the experimental group were fed ‘HELP’ diet (Sup- rently considered as a hormonally active system in the control plementary Table S1). On experimental day 60, the livers of metabolism, not only as a store of excess energy. It has been were harvested from the tested chickens after they were sac- accepted there is a close link between chronic low-grade rificed humanely. Portions of the fresh liver samples were inflammation in adipose tissue and metabolic disorders [8]. stored at –80°C until further use. Accumulated evidence indicates that adipose tissue can release hormones and adipokines which affect glucose homeostasis, Histopathological examination lipid metabolism, and inflammation. For example, inter- Fresh liver samples were dissected, rinsed with saline and leukin-6 (IL-6) is a multifunctional cytokine that plays a fixed in 10% neutral buffered formalin. The subcutaneous major role in regulating immune responses, acute phase fat was immersion-fixed in 4% formaldehyde solution for reactions and hematopoiesis in chicken and human [9]. An 24 h, then dehydrated and embedded in paraffin using a adipocyte-derived hormone of leptin can activate the JAK- standard procedure [12]. The formalin-fixed samples were STAT signaling pathway through the chicken leptin receptor routinely processed, embedded in paraffin, stained with (chLEPR) to regulate energy homeostasis [10], and suppress- hematoxylin and eosin (H&E). The stained sections were ing cytokine signaling 3 (SOCS3) plays an essential role in observed using an optical microscope, and photographs affecting systemic inflammation, insulin resistance, and were taken. Diameters of adipocyte staining were determined leptin resistance [6]. Thereby, a better understanding of the using Image-Pro Plus 6.0 software. endocrine function of adipose tissue may shed insights into the lipid metabolic disorders and the importance of inflam- Statistical analyses mation as a pathogenic pathway in the development of many Phenotypic values were presented as mean±standard devia- hallmarks of the metabolic syndrome including insulin resis- tion (mean±SD). Statistical comparisons of phenotypic values tance, leading to more rational therapy for these increasingly between the experimental and control groups were conducted prevalent disorders. by Student t-test. The statistical difference was considered as To date, as far as we know, systematic studies to detect the significant at p≤0.05 and highly significant at p≤0.01. transcriptomic changes in abdominal adipose tissue from FLHS affected (experimental) hens in comparison with healthy RNA extraction and sequencing (control) individuals are rare. To this end, we explored the Total RNA was extracted from 100 mg of adipose tissue from RNA sequencing technology to compare gene expression three FLSH experimental individuals and three control indi- profiling in the abdominal fat tissue from FLHS experimen- viduals using the RiboPure kit (Ambion, Austin, TX, USA) tal and control chickens, and to identify candidate genes according to the manufacturer's protocol. RNA integrity was and pathways functionally related to FLHS in chickens. assessed by an Agilent Bioanalyser 2100 and RNA Nano 6000 Lab chip kit (Agilent Technologies, Santa Clara, CA, MATERIALS AND METHODS USA). Sequencing libraries were generated using the NEB- Next Ultra Directional RNA Library Prep
Load more

Recommended publications
  • A University of Sussex Phd Thesis Available Online Via
    A University of Sussex PhD thesis Available online via Sussex Research Online: http://sro.sussex.ac.uk/ This thesis is protected by copyright which belongs to the author. This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the Author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the Author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Please visit Sussex Research Online for more information and further details Exploring interactions between Epstein- Barr virus transcription factor Zta and The Human Genome By IJIEL BARAK NARANJO PEREZ FERNANDEZ A Thesis submitted for the degree of Doctor of Philosophy University Of Sussex School of Life Sciences September 2017 ii I hereby declare that this thesis has not been and will not be, submitted in whole or in part to another University for the award of any other degree. Signature:…………………………..…………………………..……………………… iii Acknowledgements I want to thank Professor Alison J Sinclair for her guidance, mentoring and above all continuous patience. During the time that I’ve been part of her lab I’ve appreciated her wisdom as an educator her foresight as a scientist and tremendous love as a parent. I wish that someday soon rather than later her teachings are reflected in my person and career; hopefully inspiring others like me. Thanks to Professor Michelle West for her help whenever needed or offered. Her sincere and honest feedback, something that I only learned to appreciate after my personal scientific insight was developed.
    [Show full text]
  • Two Locus Inheritance of Non-Syndromic Midline Craniosynostosis Via Rare SMAD6 and 4 Common BMP2 Alleles 5 6 Andrew T
    1 2 3 Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and 4 common BMP2 alleles 5 6 Andrew T. Timberlake1-3, Jungmin Choi1,2, Samir Zaidi1,2, Qiongshi Lu4, Carol Nelson- 7 Williams1,2, Eric D. Brooks3, Kaya Bilguvar1,5, Irina Tikhonova5, Shrikant Mane1,5, Jenny F. 8 Yang3, Rajendra Sawh-Martinez3, Sarah Persing3, Elizabeth G. Zellner3, Erin Loring1,2,5, Carolyn 9 Chuang3, Amy Galm6, Peter W. Hashim3, Derek M. Steinbacher3, Michael L. DiLuna7, Charles 10 C. Duncan7, Kevin A. Pelphrey8, Hongyu Zhao4, John A. Persing3, Richard P. Lifton1,2,5,9 11 12 1Department of Genetics, Yale University School of Medicine, New Haven, CT, USA 13 2Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA 14 3Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, CT, USA 15 4Department of Biostatistics, Yale University School of Medicine, New Haven, CT, USA 16 5Yale Center for Genome Analysis, New Haven, CT, USA 17 6Craniosynostosis and Positional Plagiocephaly Support, New York, NY, USA 18 7Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA 19 8Child Study Center, Yale University School of Medicine, New Haven, CT, USA 20 9The Rockefeller University, New York, NY, USA 21 22 ABSTRACT 23 Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2,000 24 newborns, is treated surgically in infancy to prevent adverse neurologic outcomes. To 25 identify mutations contributing to common non-syndromic midline (sagittal and metopic) 26 craniosynostosis, we performed exome sequencing of 132 parent-offspring trios and 59 27 additional probands.
    [Show full text]
  • Molecular Characterization of Latent GDF8 Reveals Mechanisms
    Molecular characterization of latent GDF8 reveals PNAS PLUS mechanisms of activation Ryan G. Walkera,1, Jason C. McCoya,1, Magdalena Czepnika, Melanie J. Millsb,c, Adam Haggd,e, Kelly L. Waltond, Thomas R. Cottonf, Marko Hyvönenf, Richard T. Leeb,c, Paul Gregorevice,g,h,i, Craig A. Harrisond,j,2, and Thomas B. Thompsona,2 aDepartment of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH 45267; bHarvard Stem Cell Institute, Harvard University, Cambridge, MA 02138; cDepartment of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138; dBiomedicine Discovery Institute, Department of Physiology, Monash University, Clayton, VIC 3800, Australia; eBaker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia; fDepartment of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom; gDepartment of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; hDepartment of Physiology, University of Melbourne, Parkville, VIC 3010, Australia; iDepartment of Neurology, University of Washington School of Medicine, Seattle, WA 98195; and jHudson Institute of Medical Research, Clayton, VIC 3168, Australia Edited by Se-Jin Lee, Johns Hopkins University, Baltimore, MD, and approved December 7, 2017 (received for review August 22, 2017) Growth/differentiation factor 8 (GDF8), or myostatin, negatively the latent TGF-β1 crystal structure provided a molecular expla- regulates muscle mass. GDF8 is held in a latent state through nation for how latency is exerted by the prodomain via a co- interactions with its N-terminal prodomain, much like TGF-β. Using ordinated interaction between the N-terminal alpha helix (alpha- a combination of small-angle X-ray scattering and mutagenesis, 1), latency lasso, and fastener of the prodomain with type I and we characterized the interactions of GDF8 with its prodomain.
    [Show full text]
  • Revealing the Role of the Human Blood Plasma Proteome in Obesity Using Genetic Drivers
    ARTICLE https://doi.org/10.1038/s41467-021-21542-4 OPEN Revealing the role of the human blood plasma proteome in obesity using genetic drivers Shaza B. Zaghlool 1,11, Sapna Sharma2,3,4,11, Megan Molnar 2,3, Pamela R. Matías-García2,3,5, Mohamed A. Elhadad 2,3,6, Melanie Waldenberger 2,3,7, Annette Peters 3,4,7, Wolfgang Rathmann4,8, ✉ Johannes Graumann 9,10, Christian Gieger2,3,4, Harald Grallert2,3,4,12 & Karsten Suhre 1,12 Blood circulating proteins are confounded readouts of the biological processes that occur in 1234567890():,; different tissues and organs. Many proteins have been linked to complex disorders and are also under substantial genetic control. Here, we investigate the associations between over 1000 blood circulating proteins and body mass index (BMI) in three studies including over 4600 participants. We show that BMI is associated with widespread changes in the plasma proteome. We observe 152 replicated protein associations with BMI. 24 proteins also associate with a genome-wide polygenic score (GPS) for BMI. These proteins are involved in lipid metabolism and inflammatory pathways impacting clinically relevant pathways of adiposity. Mendelian randomization suggests a bi-directional causal relationship of BMI with LEPR/LEP, IGFBP1, and WFIKKN2, a protein-to-BMI relationship for AGER, DPT, and CTSA, and a BMI-to-protein relationship for another 21 proteins. Combined with animal model and tissue-specific gene expression data, our findings suggest potential therapeutic targets fur- ther elucidating the role of these proteins in obesity associated pathologies. 1 Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Doha, Qatar.
    [Show full text]
  • Supplemental Table 1. Complete Gene Lists and GO Terms from Figure 3C
    Supplemental Table 1. Complete gene lists and GO terms from Figure 3C. Path 1 Genes: RP11-34P13.15, RP4-758J18.10, VWA1, CHD5, AZIN2, FOXO6, RP11-403I13.8, ARHGAP30, RGS4, LRRN2, RASSF5, SERTAD4, GJC2, RHOU, REEP1, FOXI3, SH3RF3, COL4A4, ZDHHC23, FGFR3, PPP2R2C, CTD-2031P19.4, RNF182, GRM4, PRR15, DGKI, CHMP4C, CALB1, SPAG1, KLF4, ENG, RET, GDF10, ADAMTS14, SPOCK2, MBL1P, ADAM8, LRP4-AS1, CARNS1, DGAT2, CRYAB, AP000783.1, OPCML, PLEKHG6, GDF3, EMP1, RASSF9, FAM101A, STON2, GREM1, ACTC1, CORO2B, FURIN, WFIKKN1, BAIAP3, TMC5, HS3ST4, ZFHX3, NLRP1, RASD1, CACNG4, EMILIN2, L3MBTL4, KLHL14, HMSD, RP11-849I19.1, SALL3, GADD45B, KANK3, CTC- 526N19.1, ZNF888, MMP9, BMP7, PIK3IP1, MCHR1, SYTL5, CAMK2N1, PINK1, ID3, PTPRU, MANEAL, MCOLN3, LRRC8C, NTNG1, KCNC4, RP11, 430C7.5, C1orf95, ID2-AS1, ID2, GDF7, KCNG3, RGPD8, PSD4, CCDC74B, BMPR2, KAT2B, LINC00693, ZNF654, FILIP1L, SH3TC1, CPEB2, NPFFR2, TRPC3, RP11-752L20.3, FAM198B, TLL1, CDH9, PDZD2, CHSY3, GALNT10, FOXQ1, ATXN1, ID4, COL11A2, CNR1, GTF2IP4, FZD1, PAX5, RP11-35N6.1, UNC5B, NKX1-2, FAM196A, EBF3, PRRG4, LRP4, SYT7, PLBD1, GRASP, ALX1, HIP1R, LPAR6, SLITRK6, C16orf89, RP11-491F9.1, MMP2, B3GNT9, NXPH3, TNRC6C-AS1, LDLRAD4, NOL4, SMAD7, HCN2, PDE4A, KANK2, SAMD1, EXOC3L2, IL11, EMILIN3, KCNB1, DOK5, EEF1A2, A4GALT, ADGRG2, ELF4, ABCD1 Term Count % PValue Genes regulation of pathway-restricted GDF3, SMAD7, GDF7, BMPR2, GDF10, GREM1, BMP7, LDLRAD4, SMAD protein phosphorylation 9 6.34 1.31E-08 ENG pathway-restricted SMAD protein GDF3, SMAD7, GDF7, BMPR2, GDF10, GREM1, BMP7, LDLRAD4, phosphorylation
    [Show full text]
  • Transcriptomic Profiles of High and Low Antibody Responders to Smallpox
    Genes and Immunity (2013) 14, 277–285 & 2013 Macmillan Publishers Limited All rights reserved 1466-4879/13 www.nature.com/gene ORIGINAL ARTICLE Transcriptomic profiles of high and low antibody responders to smallpox vaccine RB Kennedy1,2, AL Oberg1,3, IG Ovsyannikova1,2, IH Haralambieva1,2, D Grill1,3 and GA Poland1,2 Despite its eradication over 30 years ago, smallpox (as well as other orthopox viruses) remains a pathogen of interest both in terms of biodefense and for its use as a vector for vaccines and immunotherapies. Here we describe the application of mRNA-Seq transcriptome profiling to understanding immune responses in smallpox vaccine recipients. Contrary to other studies examining gene expression in virally infected cell lines, we utilized a mixed population of peripheral blood mononuclear cells in order to capture the essential intercellular interactions that occur in vivo, and would otherwise be lost, using single cell lines or isolated primary cell subsets. In this mixed cell population we were able to detect expression of all annotated vaccinia genes. On the host side, a number of genes encoding cytokines, chemokines, complement factors and intracellular signaling molecules were downregulated upon viral infection, whereas genes encoding histone proteins and the interferon response were upregulated. We also identified a small number of genes that exhibited significantly different expression profiles in subjects with robust humoral immunity compared with those with weaker humoral responses. Our results provide evidence that differential gene regulation patterns may be at work in individuals with robust humoral immunity compared with those with weaker humoral immune responses. Genes and Immunity (2013) 14, 277–285; doi:10.1038/gene.2013.14; published online 18 April 2013 Keywords: Next-generation sequencing; mRNA-Seq; vaccinia virus; smallpox vaccine INTRODUCTION these 44 subjects had two samples (uninfected and vaccinia Vaccinia virus (VACV) is the immunologically cross-protective infected).
    [Show full text]
  • Circulating Protein Signatures and Causal Candidates for Type 2 Diabetes
    Diabetes Volume 69, August 2020 1843 Circulating Protein Signatures and Causal Candidates for Type 2 Diabetes Valborg Gudmundsdottir,1,2 Shaza B. Zaghlool,3 Valur Emilsson,2,4 Thor Aspelund,1,2 Marjan Ilkov,2 Elias F. Gudmundsson,2 Stefan M. Jonsson,1 Nuno R. Zilhão,2 John R. Lamb,5 Karsten Suhre,3 Lori L. Jennings,6 and Vilmundur Gudnason1,2 Diabetes 2020;69:1843–1853 | https://doi.org/10.2337/db19-1070 GENETICS/GENOMES/PROTEOMICS/METABOLOMICS The increasing prevalence of type 2 diabetes poses More than 240 genetic loci have been associated with type a major challenge to societies worldwide. Blood-based 2 diabetes in genome-wide association studies (GWAS) factors like serum proteins are in contact with every (1–5), and blood-based biomarker candidates for type organ in the body to mediate global homeostasis and 2 diabetes have begun to emerge, perhaps most notably may thus directly regulate complex processes such as the branched-chain amino acids (BCAAs) (6,7), the catab- aging and the development of common chronic dis- olism of which has recently been proposed as a novel eases. We applied a data-driven proteomics approach, treatment target for obesity-associated insulin resistance measuring serum levels of 4,137 proteins in 5,438 elderly (8). However, only fragmentary data are available for Icelanders, and identified 536 proteins associated with serum protein links to type 2 diabetes (9). While few prevalent and/or incident type 2 diabetes. We validated biomarker candidates provide much improvement in a subset of the observed associations in an independent type 2 diabetes prediction over conventional measures case-control study of type 2 diabetes.
    [Show full text]
  • Influence of WFIKKN1 on BMP1‐Mediated
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Repository of the Academy's Library Influence of WFIKKN1 on BMP1-mediated activation of latent myostatin Gyorgy€ Szlama, Viktor Vas arhelyi, Maria Trexler and Laszl o Patthy Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary Keywords The NTR domain of WFIKKN1 protein has been shown to have signifi- BMP1; heparin; latent myostatin; myostatin; cant affinity for the prodomain regions of promyostatin and latent myo- WFIKKN1 statin but the biological significance of these interactions remained unclear. In view of its role as a myostatin antagonist, we tested the assumption that Correspondence L. Patthy, Institute of Enzymology, WFIKKN1 inhibits the release of myostatin from promyostatin and/or Research Centre for Natural Sciences, latent myostatin. WFIKKN1 was found to have no effect on processing of Hungarian Academy of Sciences, Budapest, promyostatin by furin, the rate of cleavage of latent myostatin by BMP1, P.O. Box 286, H-1519, Hungary however, was significantly enhanced in the presence of WFIKKN1 and Tel: +361 382 6751 this enhancer activity was superstimulated by heparin. Unexpectedly, E-mail: [email protected] WFIKKN1 was also cleaved by BMP1 and our studies have shown that the KKN1 fragment generated by BMP1-cleavage of WFIKKN1 con- (Received 26 May 2016, revised 19 September 2016, accepted 24 October tributes most significantly to the observed enhancer activity. Analysis of a 2016) pro-TGF-b -based homology model of homodimeric latent myostatin revealed that the BMP1-cleavage sites are buried and not readily accessible doi:10.1111/febs.13938 to BMP1.
    [Show full text]
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
    BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in
    [Show full text]
  • Ligand-Specific Transcriptional Mechanisms Underlie Aryl Hydrocarbon Receptor-Mediated Developmental Toxicity of Oxygenated Pahs
    Ligand-specific transcriptional mechanisms underlie aryl hydrocarbon receptor-mediated developmental toxicity of oxygenated PAHs Goodale, B.C.* †, La Du, J. *, Tilton, S.C.* ‡, Sullivan, C.M.* §, Bisson, W.H. *, Waters, K.M. ‡ and Tanguay, R.L.* *Department of Environmental and Molecular Toxicology, the Environmental Health Sciences Center, Oregon State University, Corvallis, OR, 97330 †Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, 604 Remsen Bldg., Hanover, NH 03755 ‡Computational Biology and Bioinformatics, Pacific Northwest National Laboratory, 902 Battelle Blvd, Richland, WA 99354 §Center for Genome Research and Biocomputing, Oregon State University, Corvallis, OR, 97330 Corresponding author: Robert Tanguay, Ph.D., Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97330. Email: [email protected] Abstract Polycyclic aromatic hydrocarbons (PAHs) are priority environmental contaminants that exhibit mutagenic, carcinogenic, proinflammatory and teratogenic properties. Oxygen-substituted PAHs (OPAHs) are formed during combustion processes and via phototoxidation and biological degradation of parent (unsubstituted) PAHs. Despite their prevalence both in contaminated industrial sites and in urban air, OPAH mechanisms of action in biological systems are relatively understudied. Like parent PAHs, OPAHs exert structure-dependent mutagenic activities and activation of the aryl hydrocarbon receptor (AHR) and cytochrome p450 metabolic pathway (CYP1A). Four-ring OPAHs 1,9-benz-10-anthrone (BEZO) and benz(a)anthracene-7,12-dione (7,12-B[a]AQ) cause morphological aberrations and induce markers of oxidative stress in developing zebrafish with similar potency, but only 7,12-B[a]AQ induces robust Cyp1a protein expression. We investigated the role of the AHR in mediating the toxicity of BEZO and 7,12-B[a]AQ, and found that knockdown of AHR2 rescued developmental effects caused by both compounds.
    [Show full text]
  • GDF8) and GDF11
    JBC Papers in Press. Published on February 27, 2019 as Manuscript RA118.005831 The latest version is at http://www.jbc.org/cgi/doi/10.1074/jbc.RA118.005831 WFIKKN2 follistatin domain structure Crystal structure of the WFIKKN2 follistatin domain reveals insight into how it inhibits growth differentiation factor 8 (GDF8) and GDF11 Jason C. McCoy1, Ryan G. Walker1,#, Nathan H. Murray1,$, Thomas B. Thompson1,*. 1From the department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267. Running Title: WFIKKN2 Follistatin domain structure. #Present address: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, MA 02138 Downloaded from $Present address: Department of Biochemistry, University of Wisconsin–Madison, Madison, WI 53706, USA *To whom correspondence should be addressed: Thomas B. Thompson: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati OH 45267. http://www.jbc.org/ [email protected]; Tel. (513)-558-4517 Keywords: GDF8, Myostatin, GDF11, WFIKKN, follistatin, antagonism, X-ray crystallography, structural biology, tissue homeostasis, muscle development at University of Cincinnati/Medical Center Libraries on March 7, 2019 Abstract follistatin and FSTL3 revealed differences in both Growth differentiation factor 8 (GDF8), the FSD structure and position of residues within a.k.a. myostatin, and GDF11 are closely related the domain that are important for ligand members of the transforming growth factor β (TGF- antagonism. Taken together, our results indicate β) family. GDF8 strongly and negatively regulates that both WFIKKN and follistatin utilize their FSDs skeletal muscle growth, and GDF11 has been to block the type II receptor but do so via different implicated in various age-related pathologies such binding interactions.
    [Show full text]
  • Genomic Approach in Idiopathic Intellectual Disability Maria De Fátima E Costa Torres
    ESTUDOS DE 8 01 PDPGM 2 CICLO Genomic approach in idiopathic intellectual disability Maria de Fátima e Costa Torres D Autor. Maria de Fátima e Costa Torres D.ICBAS 2018 Genomic approach in idiopathic intellectual disability Genomic approach in idiopathic intellectual disability Maria de Fátima e Costa Torres SEDE ADMINISTRATIVA INSTITUTO DE CIÊNCIAS BIOMÉDICAS ABEL SALAZAR FACULDADE DE MEDICINA MARIA DE FÁTIMA E COSTA TORRES GENOMIC APPROACH IN IDIOPATHIC INTELLECTUAL DISABILITY Tese de Candidatura ao grau de Doutor em Patologia e Genética Molecular, submetida ao Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto Orientadora – Doutora Patrícia Espinheira de Sá Maciel Categoria – Professora Associada Afiliação – Escola de Medicina e Ciências da Saúde da Universidade do Minho Coorientadora – Doutora Maria da Purificação Valenzuela Sampaio Tavares Categoria – Professora Catedrática Afiliação – Faculdade de Medicina Dentária da Universidade do Porto Coorientadora – Doutora Filipa Abreu Gomes de Carvalho Categoria – Professora Auxiliar com Agregação Afiliação – Faculdade de Medicina da Universidade do Porto DECLARAÇÃO Dissertação/Tese Identificação do autor Nome completo _Maria de Fátima e Costa Torres_ N.º de identificação civil _07718822 N.º de estudante __ 198600524___ Email institucional [email protected] OU: [email protected] _ Email alternativo [email protected] _ Tlf/Tlm _918197020_ Ciclo de estudos (Mestrado/Doutoramento) _Patologia e Genética Molecular__ Faculdade/Instituto _Instituto de Ciências
    [Show full text]