DOCSLIB.ORG

Mafb Is Required for Islet Cell Maturation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Mafb Is Required for Islet Cell Maturation MafB is required for islet ␤ cell maturation Isabella Artner*, Bruno Blanchi†, Jeffrey C. Raum*, Min Guo*, Tomomi Kaneko‡, Sabine Cordes‡, Michael Sieweke†, and Roland Stein*§ *Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, 723 Light Hall, Nashville, TN 37232; †Centre d’Immunologie de Marseille-Luminy, Centre National de la Recherche Scientifique–Institut National de la Sante´et de la Recherche Me´dicale–Universite Mediterrane, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France; and ‡Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5 Communicated by Donald F. Steiner, The University of Chicago, Chicago, IL, January 2, 2007 (received for review December 6, 2006) Pancreatic endocrine cell differentiation depends on transcription The absence of a developmental phenotype in MafAϪ/Ϫ animals factors that also contribute in adult insulin and glucagon gene was particularly surprising, because this factor is expressed exclu- expression. Islet cell development was examined in mice lacking sively within the insulinϩ cell population produced after embryonic MafB, a transcription factor expressed in immature ␣ (glucagon؉) day (E) 13.5 that mature to become islet ␤ cells (15). The Maf basic and ␤ (insulin؉) cells and capable of activating insulin and glucagon leucine-zipper-containing transcription factor family consists of two expression in vitro. We observed that MafB؊/؊ embryos had distinct subfamilies, which differ by the presence of an N-terminal reduced numbers of insulin؉ and glucagon؉ cells throughout transactivation domain in a large Maf (i.e., MafB, MafA, c-Maf, and development, whereas the total number of endocrine cells was NRL) that is not found in a small Maf (i.e., MafF, MafG, and unchanged. Moreover, production of insulin؉ cells was delayed MafK). In contrast to MafA, all other closely related members of until embryonic day (E) 13.5 in mutant mice and coincided with the the large Maf family are involved in processes associated with cell onset of MafA expression, a MafB-related activator of insulin specification, including in the brain [i.e., MafB (16)], kidney [MafB ؉ transcription. MafA expression was only detected in the insulin (17, 18)], and immune system [cMaf (19) and MafB (18, 20)]. cell population in MafB mutants, whereas many important regu- MafB is expressed in all developing insulin- and glucagon- ؊ latory proteins continued to be expressed in insulin ␤ cells. producing cells, and then in a restricted fashion in adult ␣ cells However, Pdx1, Nkx6.1, and GLUT2 were selectively lost in these (21, 22). MafB is also capable of activating insulin- and glucagon- insulin-deficient cells between E15.5 and E18.5. MafB appears to driven transcription in non-hormone-expressing cell types in directly regulate transcription of these genes, because binding was vitro (21, 23, 24), indicating a possible redundancy with MafA observed within endogenous control region sequences. These during ␤ cell differentiation. Here we show that MafB is critical results demonstrate that MafB plays a previously uncharacterized for ␣ and ␤ cell differentiation, because the number of insulinϩ role by regulating transcription of key factors during development and glucagonϩ cells were substantially reduced in MafB mutant that are required for the production of mature ␣ and ␤ cells. animals throughout embryogenesis. Strikingly, no difference was found between the wild type and MafB mutant in total endocrine insulin ͉ MafA ͉ pancreas development cell numbers, which were assessed by pan-endocrine Islet1 (Isl1), NeuroD1, and Pax6 expression. In addition, the level of many ␣ he pancreatic islets of Langerhans are composed of ␣, ␤, ␦, (e.g., Arx, Nkx2.2, Brn4) and ␤ (Nkx2.2, Nkx6.1) cell markers was T␧, and pancreatic polypeptide (PP) cells, which produce the unchanged in ␣ and ␤ cells (both hormone-expressing and hormones glucagon, insulin, somatostatin, ghrelin, and PP, -deficient) at E15.5. However, insulin production was delayed respectively. Collectively, these hormones regulate both fuel and until the onset of MafA expression, and several other gene energy metabolism, with insulin and glucagon essential to con- products required for ␤ cell maturation and function were trolling glucose homeostasis (1). Thus, glucagon secreted from selectively reduced in hormoneϪ ␤ cells by E18.5 (Pdx1, MafA, ␣ cells stimulates the mobilization of glucose through glucone- Nkx6.1, GLUT2). These results revealed that MafB is required ogenesis and glycogenolysis, whereas ␤ cell secreted insulin for the generation of the physiologically functional ␣ and ␤ cell promotes glucose storage. Defects in ␣ and ␤ cell function play population by directly activating hormone gene transcription and a significant role in the ability of individuals with diabetes to key regulators of ␤ cell differentiation and function. maintain glycemic control. Characterization of the ␣ and ␤ cell enriched transcription factors Results and Discussion involved in regulating insulin and glucagon expression has revealed MafB؊/؊ Animals Have Reduced Numbers of Insulin؉ and Glucagon؉ not only their significance to islet function, but also to pancreas Cells, Whereas the Number of Endocrine Cells Remains Unchanged organogenesis. For example, Pdx1 is necessary for the growth of the During Development. MafB is expressed in all insulinϩ and gluca- endocrine and exocrine compartments, with pancreatic agenesis gonϩ cells during pancreas organogenesis but only in ␣ cells in the observed in pdx1 mutant mice (2, 3). Pdx1 has also been proposed adult islet (21, 22). The importance of MafB in endocrine cell to be a master regulator of ␤ cell activity, in part based on the severe formation was examined in homozygous MafB mutant animals, diabetic phenotype observed upon deletion of this factor from ␤ which die at birth because of central apnea [MafBϪ/Ϫ (16)] or renal cells in animals, a phenotype at least caused by reduced insulin and failure [krENU/krENU (17)]. Glucagonϩ cells first appear in the glucose transporter type 2 (GLUT2) expression (4). mouse at E9.5, followed by ghrelinϩ cells at E10.5 (11), insulinϩ In contrast to the profound deficiencies in pancreatic endocrine and exocrine cell development observed in the total Pdx1 knockout, BIOLOGY the loss of Pax6 (5, 6) or BETA2 [NeuroD1 (7)] only affects Author contributions: I.A. and R.S. designed research; I.A., B.B., J.C.R., M.G., and T.K. endocrine cell production. In fact, changes in endocrine cell devel- performed research; S.C. and M.S. contributed new reagents/analytic tools; I.A. and J.C.R. DEVELOPMENTAL opment are commonly found in transcription factor knockout analyzed data; and I.A. and R.S. wrote the paper. models. Thus, loss of Ngn3 leads to a severe reduction in endocrine The authors declare no conflict of interest. progenitor cells (8), whereas Nkx6.1-deficient animals display a Freely available online through the PNAS open access option. selective loss of ␤ cells (9). In contrast, there is a switch in cell Abbreviation: En, embryonic day n. lineage commitment in Arx (10), Pax4 (11), Pax6 (12), and Nkx2.2 §To whom correspondence should be addressed. E-mail: [email protected]. (11) null mutant mice. The notable exceptions are MafA and Brn4 This article contains supporting information online at www.pnas.org/cgi/content/full/ Ϫ Ϫ (13), with a deficiency only observed in adult MafA / mice, which 0700013104/DC1. were glucose intolerant and developed diabetes (14). © 2007 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0700013104 PNAS ͉ March 6, 2007 ͉ vol. 104 ͉ no. 10 ͉ 3853–3858 Downloaded by guest on September 28, 2021 Fig. 1. MafBϪ/Ϫ pancreata have fewer insulinϩ and glucagonϩ cells. (A) Immunofluorescence staining for insulin (green) and glucagon (red) was performed in wild-type and MafBϪ/Ϫ pancreas at E10.5 (glucagon only), E12.5, E13.5, and E15.5. Insulinϩ cells are indicated by an arrow at E12.5. Notably, insulin expression was delayed until E13.5 in the MafB mutant, whereas glucagon was observed at all stages. (B) Quantification of insulinϩ and glucagonϩ cells in wild-type (black bars) and MafBϪ/Ϫ (gray bars) embryos. Because the wild-type and heterozygous MafB embryos showed no difference in hormone cell numbers (data not shown), both were incorporated into the ‘‘wild-type’’ data. The average number of cells per section is shown Ϯ SD, with the asterisk denoting the significance between wild-type and mutant embryos (P Ͻ 0.02). (Scale bars: 20 ␮M.) cells at E11.5 (25), and somatostatinϩ and PPϩ at E15.5 and E18.5, The size and gross appearance of the MafBϪ/Ϫ embryonic respectively (26). MafB is expressed in the distinct first- and pancreata was normal, and insulin- and glucagon-producing cells second-phase insulinϩ and glucagonϩ cells made during develop- were detected (Fig. 1A). However, the number of glucagonϩ cells ment, with only second-phase cells producing the ␣ and ␤ cells that was drastically lower at all embryonic stages when compared mature and populate the islet (27). with the wild type (Fig. 1B). Moreover, insulinϩ cells were not Fig. 2. Total endocrine cell numbers are unchanged in MafBϪ/Ϫ pancreata. (A) Immunofluorescence staining of E15.5 wild-type and MafB mutant pancreas sections with ␣-Isl1 (green), ␣-insulin (red), ␣-Pax6 (green), and/or ␣-glucagon (red). Nuclei were stained with YoPro1 (blue). In the mutant, sections containing a larger number of glucagon and insulin producing cells were selected to illustrate Isl1 and Pax6 coexpression, and not the quantitative decrease in insulinϩ or glucagonϩ cells found between wild-type and MafBϪ/Ϫ mice. (B) Quantification of Isl1ϩ cells in wild-type (black bars) and MafBϪ/Ϫ (gray bars) embryos. No significant difference was found in Isl1ϩ cell numbers at E12.5, E13.5, E15.5, and E18.5. The average number of cells per section is shown Ϯ SD. (C) The real-time PCR mRNA levels of isl1, pax6, and neuroD1 are shown as the percentage of wild type (100%) at E15.5 and E18.5. (Scale bar: 20 ␮M.) 3854 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0700013104 Artner et al.
Load more

Recommended publications
  • RBP-J Signaling − Cells Through Notch Novel IRF8-Controlled
    Sca-1+Lin−CD117− Mesenchymal Stem/Stromal Cells Induce the Generation of Novel IRF8-Controlled Regulatory Dendritic Cells through Notch −RBP-J Signaling This information is current as of September 25, 2021. Xingxia Liu, Shaoda Ren, Chaozhuo Ge, Kai Cheng, Martin Zenke, Armand Keating and Robert C. H. Zhao J Immunol 2015; 194:4298-4308; Prepublished online 30 March 2015; doi: 10.4049/jimmunol.1402641 Downloaded from http://www.jimmunol.org/content/194/9/4298 Supplementary http://www.jimmunol.org/content/suppl/2015/03/28/jimmunol.140264 http://www.jimmunol.org/ Material 1.DCSupplemental References This article cites 59 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/194/9/4298.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 25, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Sca-1+Lin2CD1172 Mesenchymal Stem/Stromal Cells Induce the Generation of Novel IRF8-Controlled Regulatory Dendritic Cells through Notch–RBP-J Signaling Xingxia Liu,*,1 Shaoda Ren,*,1 Chaozhuo Ge,* Kai Cheng,* Martin Zenke,† Armand Keating,‡,x and Robert C.
    [Show full text]
  • Microglia Emerge from Erythromyeloid Precursors Via Pu.1- and Irf8-Dependent Pathways
    ART ic LE S Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways Katrin Kierdorf1,2, Daniel Erny1, Tobias Goldmann1, Victor Sander1, Christian Schulz3,4, Elisa Gomez Perdiguero3,4, Peter Wieghofer1,2, Annette Heinrich5, Pia Riemke6, Christoph Hölscher7,8, Dominik N Müller9, Bruno Luckow10, Thomas Brocker11, Katharina Debowski12, Günter Fritz1, Ghislain Opdenakker13, Andreas Diefenbach14, Knut Biber5,15, Mathias Heikenwalder16, Frederic Geissmann3,4, Frank Rosenbauer6 & Marco Prinz1,17 Microglia are crucial for immune responses in the brain. Although their origin from the yolk sac has been recognized for some time, their precise precursors and the transcription program that is used are not known. We found that mouse microglia were derived from primitive c-kit+ erythromyeloid precursors that were detected in the yolk sac as early as 8 d post conception. + lo − + − + These precursors developed into CD45 c-kit CX3CR1 immature (A1) cells and matured into CD45 c-kit CX3CR1 (A2) cells, as evidenced by the downregulation of CD31 and concomitant upregulation of F4/80 and macrophage colony stimulating factor receptor (MCSF-R). Proliferating A2 cells became microglia and invaded the developing brain using specific matrix metalloproteinases. Notably, microgliogenesis was not only dependent on the transcription factor Pu.1 (also known as Sfpi), but also required Irf8, which was vital for the development of the A2 population, whereas Myb, Id2, Batf3 and Klf4 were not required. Our data provide cellular and molecular insights into the origin and development of microglia. Microglia are the tissue macrophages of the brain and scavenge dying have the ability to give rise to microglia and macrophages in vitro cells, pathogens and molecules using pattern recognition receptors and in vivo under defined conditions.
    [Show full text]
  • Roles and Regulation of Transcription Factor Mafa in Islet Β-Cells
    Endocr. J./ S. ARAMATA et al.: INSULIN TRANSCRIPTION AND MafA doi: 10.1507/endocrj.KR-101 REVIEW Roles and Regulation of Transcription Factor MafA in Islet β-cells * SHINSAKU ARAMATA, SONG-IEE HAN AND KOHSUKE KATAOKA Graduate School of Biological Science, Nara Institute of Science and Technology, 8916-5 Takayama-cho, Ikoma, Nara 630-0192, Japan ＊Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki 305-8572, Japan. Released online August 30, 2007 Correspondence to: Kohsuke KATAOKA, Graduate School of Biological Science, Nara Institute of Science and Technology, 8916-5 Takayama-cho, Ikoma, Nara 630-0192, Japan Abstract. Insulin is a critical hormone in the regulation of blood glucose levels. It is produced exclusively by pancreatic islet β-cells. β-cell-enriched transcription factors, such as Pdx1 and Beta2, have dual roles in the activation of the insulin gene promoter establishing β-cell-specific insulin expression, and in the regulation of β-cell differentiation. It was shown that MafA, a β-cell-specific member of the Maf family of transcription factors, binds to the conserved C1/RIPE3b element of the insulin promoter. The Maf family proteins regulate tissue-specific gene expression and cell differentiation in a wide variety of tissues. MafA acts synergistically with Pdx1 and Beta2 to activate the insulin gene promoter, and mice with a targeted deletion of mafA develop age-dependent diabetes. MafA also regulates genes involved in β-cell function such as Glucose transporter 2, Glucagons-like peptide 1 receptor, and Prohormone convertase 1/3. The abundance of MafA in β-cells is regulated at both the transcriptional and post-translational levels by glucose and oxidative stress.
    [Show full text]
  • Differential Expression of Vitamin D Binding Protein in Thyroid Cancer Health Disparities
    www.oncotarget.com Oncotarget, 2021, Vol. 12, (No. 7), pp: 596-607 Research Paper Differential expression of Vitamin D binding protein in thyroid cancer health disparities Brittany Mull1, Ryan Davis2,3, Iqbal Munir4, Mia C. Perez5, Alfred A. Simental6 and Salma Khan2,3,6,7 1Harbor UCLA Medical Center, Torrance, CA 90502, USA 2Division of Biochemistry, Loma Linda, CA 92350, USA 3Center for Health Disparities & Molecular Medicine, Loma Linda, CA 92350, USA 4Riverside University Health System, Moreno Valley, CA 92555, USA 5Department of Pathology & Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA 6Department of Otolaryngology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA 7Department of Internal Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA Correspondence to: Salma Khan, email: [email protected] Keywords: DBP; thyroid cancer; health disparities Received: November 16, 2020 Accepted: March 05, 2021 Published: March 30, 2021 Copyright: © 2021 Mull et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Thyroid cancer incidence, recurrence, and death rates are higher among Filipino Americans than European Americans. We propose that vitamin D binding protein (DBP) with multifunctionality with ethnic variability plays a key role within different ethnicities. In this study, we determined the correlation between differential DBP expression in tumor tissues and cancer staging in Filipino Americans versus European Americans. We assayed DBP expression by immunohistochemistry and analyzed the data with confocal microscopy on 200 thyroid cancer archival tissue samples obtained from both ethnicities.
    [Show full text]
  • Prox1regulates the Subtype-Specific Development of Caudal Ganglionic
    The Journal of Neuroscience, September 16, 2015 • 35(37):12869–12889 • 12869 Development/Plasticity/Repair Prox1 Regulates the Subtype-Specific Development of Caudal Ganglionic Eminence-Derived GABAergic Cortical Interneurons X Goichi Miyoshi,1 Allison Young,1 Timothy Petros,1 Theofanis Karayannis,1 Melissa McKenzie Chang,1 Alfonso Lavado,2 Tomohiko Iwano,3 Miho Nakajima,4 Hiroki Taniguchi,5 Z. Josh Huang,5 XNathaniel Heintz,4 Guillermo Oliver,2 Fumio Matsuzaki,3 Robert P. Machold,1 and Gord Fishell1 1Department of Neuroscience and Physiology, NYU Neuroscience Institute, Smilow Research Center, New York University School of Medicine, New York, New York 10016, 2Department of Genetics & Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, 3Laboratory for Cell Asymmetry, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan, 4Laboratory of Molecular Biology, Howard Hughes Medical Institute, GENSAT Project, The Rockefeller University, New York, New York 10065, and 5Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724 Neurogliaform (RELNϩ) and bipolar (VIPϩ) GABAergic interneurons of the mammalian cerebral cortex provide critical inhibition locally within the superficial layers. While these subtypes are known to originate from the embryonic caudal ganglionic eminence (CGE), the specific genetic programs that direct their positioning, maturation, and integration into the cortical network have not been eluci- dated. Here, we report that in mice expression of the transcription factor Prox1 is selectively maintained in postmitotic CGE-derived cortical interneuron precursors and that loss of Prox1 impairs the integration of these cells into superficial layers. Moreover, Prox1 differentially regulates the postnatal maturation of each specific subtype originating from the CGE (RELN, Calb2/VIP, and VIP).
    [Show full text]
  • Temporal Mapping of CEBPA and CEBPB Binding
    Downloaded from genome.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Temporal mapping of CEBPA and CEBPB binding during liver regeneration reveals dynamic occupancy and specific regulatory codes for homeostatic and cell cycle gene batteries Janus Schou Jakobsen1,2,3,*, Johannes Waage1,2,3,4, Nicolas Rapin1,2,3,4, Hanne Cathrine Bisgaard5, Fin Stolze Larsen6, Bo Torben Porse1,2,3,* 1 The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, DK2200 Copenhagen, Denmark; 2 Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen, Denmark; 3 The Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, DK2200 Copenhagen Denmark; 4 The Bioinformatics Centre, University of Copenhagen, DK2200, Copenhagen, Denmark; 5 Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, DK- 2100 Copenhagen, Denmark; 6 Department of Hepatology, Rigshospitalet, DK2200 Copenhagen, Denmark. JW: [email protected]; NR: [email protected]; HCB: [email protected]; FSL: [email protected] * Corresponding authors: BTP: [email protected]; JSJ: [email protected], The Finsen Laboratory, Ole Maaløesvej 5, Copenhagen Biocenter, University of Copenhagen, DK2200 Copenhagen, Denmark. Telephone: +45 3545 6023 Running title: Regulation of liver regeneration Keywords: Temporal ChIP-seq, dynamic binding, liver regeneration, C/EBPalpha, C/EBPbeta, transcriptional networks 1 Downloaded from genome.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Abstract Dynamic shifts in transcription factor binding are central to the regulation of biological processes by allowing rapid changes in gene transcription.
    [Show full text]
  • Transcriptional Control of Microglia Phenotypes in Health and Disease
    REVIEW SERIES: GLIA AND NEURODEGENERATION The Journal of Clinical Investigation Series Editors: Marco Colonna and David Holtzmann Transcriptional control of microglia phenotypes in health and disease Inge R. Holtman,1,2 Dylan Skola,1 and Christopher K. Glass1,3 1Department of Cellular and Molecular Medicine, UCSD, San Diego, California, USA. 2Department of Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands. 3Department of Medicine, UCSD, San Diego, California, USA. Microglia are the main resident macrophage population of the CNS and perform numerous functions required for CNS development, homeostasis, immunity, and repair. Many lines of evidence also indicate that dysregulation of microglia contributes to the pathogenesis of neurodegenerative and behavioral diseases. These observations provide a compelling argument to more clearly define the mechanisms that control microglia identity and function in health and disease. In this Review, we present a conceptual framework for how different classes of transcription factors interact to select and activate regulatory elements that control microglia development and their responses to internal and external signals. We then describe functions of specific transcription factors in normal and pathological contexts and conclude with a consideration of open questions to be addressed in the future. Introduction regulatory control necessary to generate cell type–specific programs Microglia are tissue-resident macrophages that perform CNS- of gene expression. This additional information is provided by distal specific functions (1). They derive from a unique lineage of eryth- regulatory elements called enhancers (12). Enhancers represent the romyeloid precursors (EMPs) in the yolk sac and fetal liver (2). most numerous binding sites for LDTFs and signal-dependent tran- EMPs infiltrate the brain during early development, differentiate scription factors (SDTFs), and are major sites for the integration of into microglia, and maintain their population by self-renewal (3).
    [Show full text]
  • Calculating the Statistical Significance of Rare Variants Causal for Mendelian and Complex Disorders
    bioRxiv preprint doi: https://doi.org/10.1101/103218; this version posted January 25, 2017. 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. Calculating the statistical significance of rare variants causal for Mendelian and complex disorders Aliz R Rao1*, Stanley F Nelson1,2,3† *Correspondence: [email protected] †Email: [email protected] 1Department of Human Genetics, University of California, Los Angeles, Los Angeles, California, USA. 2Department of Psychiatry and Biobehavioral Sciences at the David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. 3Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA. 1 bioRxiv preprint doi: https://doi.org/10.1101/103218; this version posted January 25, 2017. 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 With the expanding use of next-gen sequencing (NGS) to diagnose the thousands of rare Mendelian genetic diseases, it is critical to be able to interpret individual DNA variation. We developed a general method to better interpret the likelihood that a rare variant is disease causing if observed in a given gene or genic region mapping to a described protein domain, using genome-wide information from a large control sample.
    [Show full text]
  • LPS Induces the Degradation of Programmed Cell Death Protein 4
    THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 289, NO. 33, pp. 22980–22990, August 15, 2014 © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. LPS Induces the Degradation of Programmed Cell Death Protein 4 (PDCD4) to Release Twist2, Activating c-Maf Transcription to Promote Interleukin-10 Production* Received for publication, April 10, 2014, and in revised form, June 27, 2014 Published, JBC Papers in Press, June 30, 2014, DOI 10.1074/jbc.M114.573089 Mirjam W. M. van den Bosch‡1, Eva Palsson-Mcdermott‡, Derek S. Johnson§, and Luke A. J. O’Neill‡ From the ‡School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland and the §Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 Background: LPS-induced PDCD4 degradation leads to IL-10 induction. Results: LPS-induced PDCD4 degradation results in release of Twist2, resulting in c-Maf induction and IL-10 production. Conclusion: The PDCD4/Twist2 interaction has an important anti-inflammatory role in LPS signaling. Significance: This study reports the mechanism of PDCD4/Twist2 interaction and provides a new insight of IL-10 production Downloaded from via suppression of PDCD4/Twist2 interaction. Programmed cell death protein 4 (PDCD4) is a tumor sup- ent complexes, mTOR complex 1 (mTORC1) and mTORC2. pressor and has also been shown to suppress production of the mTORC1 comprises mTOR in a complex with mLST8 http://www.jbc.org/ immunomodulatory cytokine IL-10. The precise role of PDCD4 (mammalian lethal with SEC13 protein 8), PRAS40 (proline- in IL-10 induction in macrophages is still not fully understood.
    [Show full text]
  • The Basic Motif-Leucine Zipper Transcription Factor Nrl Can
    Proc. Natl. Acad. Sci. USA Vol. 93, pp. 191-195, January 1996 Genetics The basic motif-leucine zipper transcription factor Nrl can positively regulate rhodopsin gene expression (retinal genes/retinal diseases/maf oncogene family/DNA-binding protein) ALNAWAZ REHEMTULLA*t, RON WARWARt, RAJAN KUMAR§, XIAODONG Jlt, DONALD J. ZACK§P, AND ANAND SWAROOPt,* *,tt *Howard Hughes Medical Institute and Departments of tOphthalmology and **Human Genetics, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105; and Departments of §Ophthalmology, 1Molecular Biology and Genetics, and liNeurosciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287 Communicated by James V. Neel, University of .Michigan Medical School, Ann Arbor, MI, August 31, 1995 ABSTRACT The retinal protein Nrl belongs to a distinct the bZIP family of DNA-binding proteins (14). It is highly subfamily of basic motif-leucine zipper DNA-binding proteins conserved between mouse and man and demonstrates a retina- and has been shown to bind extended AP-1-like sequence specific pattern of expression on Northern analysis (11, 13). elements as a homo- or heterodimer. Here, we demonstrate The Nrl protein shows strong sequence homology to the v-maf that Nrl can positively regulate the expression of the photo- oncogene product (15). Maf and Nrl define a distinct subfamily receptor cell-specific gene rhodopsin. Electrophoretic mobil- of bZIP proteins that includes the c-mafprotooncogene prod- ity-shift analysis reveals that a protein(s) in nuclear extracts uct (16), several other Maf proteins (17, 18), the small subunit from bovine retina and the Y79 human retinoblastoma cell p18 of the erythroid transcription factor NF-E2 (19), and the line binds to a conserved Nrl response element (NRE) in the product of the segmentation gene kriesler (kr) (20).
    [Show full text]
  • Mafa Enables Pdx1 to Effectively Convert Pancreatic Islet Progenitors and Committed Islet A-Cells Into B-Cells in Vivo
    Diabetes Volume 66, May 2017 1293 Mafa Enables Pdx1 to Effectively Convert Pancreatic Islet Progenitors and Committed Islet a-Cells Into b-Cells In Vivo Taka-aki Matsuoka,1 Satoshi Kawashima,1 Takeshi Miyatsuka,1,2 Shugo Sasaki,1 Naoki Shimo,1 Naoto Katakami,1 Dan Kawamori,1 Satomi Takebe,1 Pedro L. Herrera,3 Hideaki Kaneto,4 Roland Stein,5 and Iichiro Shimomura1 Diabetes 2017;66:1293–1300 | DOI: 10.2337/db16-0887 Among the therapeutic avenues being explored for re- including coronary and renal disease. A variety of innova- placement of the functional islet b-cell mass lost in tive approaches are being explored to produce b-cells from type 1 diabetes (T1D), reprogramming of adult cell types embryonic stem cells (1,2) and adult cell types (3–5). A into new b-cells has been actively pursued. Notably, supposition in these efforts involves producing conditions mouse islet a-cells will transdifferentiate into b-cells un- that correctly regulate the transcription factor networks der conditions of near b-cell loss, a condition similar to required in programming pancreatic progenitor cells into ISLET STUDIES a T1D. Moreover, human islet -cells also appear to poised b-cells and subsequently controlling mature islet cell func- for reprogramming into insulin-positive cells. Here we tion. These include transcription factors like Pdx1 (6–10), have generated transgenic mice conditionally expressing which is essential in the formation of early pancreatic ep- the islet b-cell–enriched Mafa and/or Pdx1 transcription ithelium, developing b-cells and adult islet b-cells, as well factors to examine their potential to transdifferentiate as neurogenin 3 (Ngn3) (11–13), which is required during embryonic pan–islet cell Ngn3-positive progenitors and embryogenesis for specification of all islet cell types (i.e., the later glucagon-positive a-cell population into b-cells.
    [Show full text]
  • University of Cincinnati
    UNIVERSITY OF CINCINNATI Date: 5/8/06 I, Emily E. Bosco Hereby submit this work as part of the requirements for the degree of: Doctor of Philosophy in: Cell and Molecular Biology It is entitled: RB Modifies the Therapeutic Response of Breast Cancer This work and its defense approved by: Chair: Erik Knudsen Sue Heffelfinger Kathy Hepner-Goss Sohaib Khan Yolanda Sanchez The Retinoblastoma Tumor Suppressor Modifies the Therapeutic Response of Breast Cancer A dissertation submitted to the Division of Research and Advanced Studies of the University of Cincinnati in partial fulfillment of the requirements for the degree of Doctorate of Philosophy (Ph.D.) in the Department of Cell Biology, Neurobiology, and Anatomy of the College of Medicine 5/8/06 by Emily Elizabeth Bosco B.S. University of Notre Dame, 2001 Committee Chairman: Erik S. Knudsen Ph.D. Abstract: The retinoblastoma tumor suppressor (RB) is functionally inactivated in the majority of human cancers, and nearly half of all breast cancers. Here, we investigate the consequence of RB loss on the response to DNA damage and anti-estrogenic therapies used in the treatment of breast cancer. Initially, we demonstrate that downstream RB targets are severely mis-regulated following acute deletion in adult primary cells causing abrogation of the DNA damage checkpoint and consequently, accumulation of secondary DNA lesions upon treatment with chemotherapeutics. Additionally, we found that RB modifies the DNA repair response in adult primary fibroblasts, such that RB-deficient cells are able to repair UV-induced lesions at an accelerated rate. These initial studies reveal that RB loss in primary cells modifies the response to DNA damage by promoting aberrant replication and inappropriately accelerating repair, both of which may ultimately sensitize cells to DNA damaging therapies.
    [Show full text]