DOCSLIB.ORG

The Role of Gli3 in Inflammation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Role of Gli3 in Inflammation University of New Hampshire University of New Hampshire Scholars' Repository Doctoral Dissertations Student Scholarship Winter 2020 THE ROLE OF GLI3 IN INFLAMMATION Stephan Josef Matissek University of New Hampshire, Durham Follow this and additional works at: https://scholars.unh.edu/dissertation Recommended Citation Matissek, Stephan Josef, "THE ROLE OF GLI3 IN INFLAMMATION" (2020). Doctoral Dissertations. 2552. https://scholars.unh.edu/dissertation/2552 This Dissertation is brought to you for free and open access by the Student Scholarship at University of New Hampshire Scholars' Repository. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of University of New Hampshire Scholars' Repository. For more information, please contact [email protected]. THE ROLE OF GLI3 IN INFLAMMATION BY STEPHAN JOSEF MATISSEK B.S. in Pharmaceutical Biotechnology, Biberach University of Applied Sciences, Germany, 2014 DISSERTATION Submitted to the University of New Hampshire in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy In Biochemistry December 2020 This dissertation was examined and approved in partial fulfillment of the requirement for the degree of Doctor of Philosophy in Biochemistry by: Dissertation Director, Sherine F. Elsawa, Associate Professor Linda S. Yasui, Associate Professor, Northern Illinois University Paul Tsang, Professor Xuanmao Chen, Assistant Professor Don Wojchowski, Professor On October 14th, 2020 ii ACKNOWLEDGEMENTS First, I want to express my absolute gratitude to my advisor Dr. Sherine Elsawa. Without her help, incredible scientific knowledge and amazing guidance I would not have been able to achieve what I did. It was her encouragement and believe in me that made me overcome any scientific struggles and strengthened my self-esteem as a human being and as a scientist. There was never a time where her door was not open, and she was always reachable even at late hours or holidays. Her heartful manner and positive presence was one of the main reasons that kept me motivated in my Ph.D. studies and her scientific skillset and plethora of knowledge was always a standard I tried to achieve. Dr. Elsawa taught me that no goal is too big to be reached as long as I keep working consistently ,always try to improve and always believe in myself and it is without a doubt that without her I would not be sitting here finishing my dissertation. I consider my Ph.D. as one of the biggest achievements in my life which I would have never reached without the guiding hand of Dr. Elsawa. Besides Dr. Elsawa I also would like to deeply express my gratitude to my committee members, Dr. Linda Yasui, Dr. Don Wojchowski, Dr. Paul Tsang and Dr. Xuanmao Chen for their professional insights, kind help and amazing scientific suggestions. iii This research was supported by grant P20GM113131 from the National Institute of General Medical Sciences of the NIH. I also would like to thank the NIU Office of Vice President for Research and Innovation Partnerships (OVPRIP) for financial support for this project. Additionally, I would like to thank UNH for proving travel funds which allowed me to attend several conferences. These conferences were very valuable experiences from which I gained many important connections. Finally, I want to thank UNH for providing graduate student teaching assistantships and linked financial support. I absolutely want to thank my family and friends for their never-ending emotional (but also financial) support in my studies. Doing a Ph.D. can be very exhausting and without them supporting me and believing in me I would have never finished my studies. In particular, I want to thank following people: My mother, for always believing in me especially when I had trouble believing in myself and for being the most supportive person in my life. There was never a struggle that I faced without having my mother’s encouraging words in my ear. She is my role model for how to deal with problems since without her teaching me to be patient with myself and solving issues by putting one foot in front of the other I would not be where I am today. My sister Karina for being an extremely accomplished scientist who never fails to achieve any goal she sets. Her love to science motivated me to start my Ph.D. My sister Astrid whose discipline seeks its equal and motivated me to push through any late-night shifts in lab. My father, for being such a tough person and him seeing how he iv pushed through problems gave me, besides other things, the strength to push through mine. I also want to express my gratitude to past and present members of the Elsawa Lab. I want to thank for all the professional help provided, for the fun times we shared and contributions to my project. v TABLE OF CONTENT ACKNOWLEDGEMENTS ............................................................................................... iii TABLE OF CONTENT ....................................................................................................vi LIST OF FIGURES..........................................................................................................ix ABSTRACT .....................................................................................................................xi CHAPTER 1 .................................................................................................................... 1 Inflammation, a double-edged sword .............................................................................. 1 Acute inflammation; the good response ....................................................................... 2 General principles of an acute inflammatory response ................................................ 2 Principles of inflammation: para-inflammation .............................................................. 3 Principles of inflammation: acute inflammation ............................................................ 4 Exogenous stimuli ........................................................................................................ 5 Infection .................................................................................................................... 5 Toll-like receptors (TLRs) and their signaling pathways ........................................... 6 Extracellular TLRs ................................................................................................. 7 TLR2 only complexes with TLR1 or TLR6.......................................................... 7 TLR4 .................................................................................................................. 9 MYD88 pathway .................................................................................................. 10 TRIF pathway ...................................................................................................... 11 TLR5 ................................................................................................................ 12 TLR10 .............................................................................................................. 13 Intracellular TLRs ................................................................................................ 13 TLR3 ................................................................................................................ 13 TLR7/8 ............................................................................................................. 14 TLR9 ................................................................................................................ 15 Endogenous stimuli .................................................................................................... 17 Role of adaptive immune system in inflammation ...................................................... 18 Chronic inflammation, the bad one ............................................................................ 19 vi Infections related to chronic inflammation .............................................................. 20 Cellular stress related to chronic inflammation (DAMPs) ........................................ 21 Molecular characteristics involved in diseases caused by chronic inflammation ........................................................................................................... 22 Autoimmunity ....................................................................................................... 22 Cancer ................................................................................................................. 25 Molecular pathways linking chronic inflammation to cancer ............................. 26 NF-κB, STAT and SHH........................................................................................ 26 GLI3: A mediator of genetic diseases, development and cancer ............................... 28 Regulation and Structure ........................................................................................ 29 Hedgehog ligands and their function ................................................................... 29 Classic (canonical) Hh signaling .......................................................................... 30 In mammals ......................................................................................................... 31 Non-classical (non-canonical) HH signaling ........................................................ 34 Regulation of GLI3.................................................................................................
Load more

Recommended publications
  • Methylation Status of Vitamin D Receptor Gene Promoter in Adrenocortical Carcinoma
    UNIVERSITÀ DEGLI STUDI DI PADOVA DEPARTMENT OF CARDIAC, THORACIC AND VASCULAR SCIENCES Ph.D Course Medical Clinical and Experimental Sciences Curriculum Clinical Methodology, Endocrinological, Diabetological and Nephrological Sciences XXIX° SERIES METHYLATION STATUS OF VITAMIN D RECEPTOR GENE PROMOTER IN ADRENOCORTICAL CARCINOMA Coordinator: Ch.mo Prof. Annalisa Angelini Supervisor: Ch.mo Prof. Francesco Fallo Ph.D Student: Andrea Rebellato TABLE OF CONTENTS SUMMARY 3 INTRODUCTION 4 PART 1: ADRENOCORTICAL CARCINOMA 4 1.1 EPIDEMIOLOGY 4 1.2 GENETIC PREDISPOSITION 4 1.3 CLINICAL PRESENTATION 6 1.4 DIAGNOSTIC WORK-UP 7 1.4.1 Biochemistry 7 1.4.2 Imaging 9 1.5 STAGING 10 1.6 PATHOLOGY 11 1.7 MOLECULAR PATHOLOGY 14 1.7.1 DNA content 15 1.7.2 Chromosomal aberrations 15 1.7.3 Differential gene expression 16 1.7.4 DNA methylation 17 1.7.5 microRNAs 18 1.7.6 Gene mutations 19 1.8 PATHOPHYSIOLOGY OF MOLECULAR SIGNALLING 21 PATHWAYS 1.8.1 IGF-mTOR pathway 21 1.8.2 WNTsignalling pathway 22 1.8.3 Vascular endothelial growth factor 23 1.9 THERAPY 24 1.9.1 Surgery 24 1.9.2 Adjuvant Therapy 27 1.9.2.1 Mitotane 27 1.9.2.2 Cytotoxic chemotherapy 30 1.9.2.3 Targeted therapy 31 1.9.2.4 Therapy for hormone excess 31 1.9.2.5 Radiation therapy 32 1.9.2.6 Other local therapies 32 1.10 PROGNOSTIC FACTORS AND PREDICTIVE MARKERS 32 PART 2: VITAMIN D 35 2.1 VITAMIN D AND ITS BIOACTIVATION 35 2.2 THE VITAMIN D RECEPTOR 37 2.3 GENOMIC MECHANISM OF 1,25(OH)2D3-VDR COMPLEX 38 2.4 CLASSICAL ROLES OF VITAMIN D 40 2.4.1 Intestine 40 2.4.2 Kidney 41 2.4.3 Bone 41 2.5 PLEIOTROPIC
    [Show full text]
  • Non-Canonical Activation of Hedgehog in Prostate Cancer Cells Mediated by the Interaction of Transcriptionally Active Androgen Receptor Proteins with Gli3
    Oncogene (2018) 37:2313–2325 https://doi.org/10.1038/s41388-017-0098-7 ARTICLE Non-canonical activation of hedgehog in prostate cancer cells mediated by the interaction of transcriptionally active androgen receptor proteins with Gli3 1 1,2 2 1 1 1 2,3 Na Li ● Sarah Truong ● Mannan Nouri ● Jackson Moore ● Nader Al Nakouzi ● Amy Anne Lubik ● Ralph Buttyan Received: 19 July 2017 / Revised: 18 October 2017 / Accepted: 29 November 2017 / Published online: 12 February 2018 © The Author(s) 2018. This article is published with open access Abstract Hedgehog (Hh) is an oncogenic signaling pathway that regulates the activity of Gli transcription factors. Canonical Hh is a Smoothened-(Smo-) driven process that alters the post-translational processing of Gli2/Gli3 proteins. Though evidence supports a role for Gli action in prostate cancer (PCa) cell growth and progression, there is little indication that Smo is involved. Here we describe a non-canonical means for activation of Gli transcription in PCa cells mediated by the binding of transcriptionally-active androgen receptors (ARs) to Gli3. Androgens stimulated reporter expression from a Gli-dependent promoter in a variety of AR + PCa cells and this activity was suppressed by an anti-androgen, Enz, or by AR knockdown. 1234567890();,: Androgens also upregulated expression of endogenous Gli-dependent genes. This activity was associated with increased intranuclear binding of Gli3 to AR that was antagonized by Enz. Fine mapping of the AR binding domain on Gli2 showed that AR recognizes the Gli protein processing domain (PPD) in the C-terminus. Mutations in the arginine-/serine repeat elements of the Gli2 PPD involved in phosphorylation and ubiquitinylation blocked the binding to AR.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Loss of the PTCH1 Tumor Suppressor Defines a New
    Banerjee et al. J Transl Med (2019) 17:246 https://doi.org/10.1186/s12967-019-1995-z Journal of Translational Medicine RESEARCH Open Access Loss of the PTCH1 tumor suppressor defnes a new subset of plexiform fbromyxoma Sudeep Banerjee1,2, Christopher L. Corless3, Markku M. Miettinen4, Sangkyu Noh1, Rowan Ustoy1, Jessica L. Davis3, Chih‑Min Tang1, Mayra Yebra1, Adam M. Burgoyne5 and Jason K. Sicklick1* Abstract Background: Plexiform fbromyxoma (PF) is a rare gastric tumor often confused with gastrointestinal stromal tumor. These so‑called “benign” tumors often present with upper GI bleeding and gastric outlet obstruction. It was recently demonstrated that approximately one‑third of PF have activation of the GLI1 oncogene, a transcription factor in the hedgehog (Hh) pathway, via a MALAT1‑GLI1 fusion protein or GLI1 up‑regulation. Despite this discovery, the biology of most PFs remains unknown. Methods: Next generation sequencing (NGS) was performed on formalin‑fxed parafn‑embedded (FFPE) samples of PF specimens collected from three institutions (UCSD, NCI and OHSU). Fresh frozen tissue from one tumor was utilized for in vitro assays, including quantitative RT‑PCR and cell viability assays following drug treatment. Results: Eight patients with PF were identifed and 5 patients’ tumors were analyzed by NGS. An index case had a mono‑allelic PTCH1 deletion of exons 15–24 and a second case, identifed in a validation cohort, also had a PTCH1 gene loss associated with a suspected long‑range chromosome 9 deletion. Building on the role of Hh signaling in PF, PTCH1, a tumor suppressor protein, functions upstream of GLI1. Loss of PTCH1 induces GLI1 activation and down‑ stream gene transcription.
    [Show full text]
  • Evidence for Differential Alternative Splicing in Blood of Young Boys With
    Stamova et al. Molecular Autism 2013, 4:30 http://www.molecularautism.com/content/4/1/30 RESEARCH Open Access Evidence for differential alternative splicing in blood of young boys with autism spectrum disorders Boryana S Stamova1,2,5*, Yingfang Tian1,2,4, Christine W Nordahl1,3, Mark D Shen1,3, Sally Rogers1,3, David G Amaral1,3 and Frank R Sharp1,2 Abstract Background: Since RNA expression differences have been reported in autism spectrum disorder (ASD) for blood and brain, and differential alternative splicing (DAS) has been reported in ASD brains, we determined if there was DAS in blood mRNA of ASD subjects compared to typically developing (TD) controls, as well as in ASD subgroups related to cerebral volume. Methods: RNA from blood was processed on whole genome exon arrays for 2-4–year-old ASD and TD boys. An ANCOVA with age and batch as covariates was used to predict DAS for ALL ASD (n=30), ASD with normal total cerebral volumes (NTCV), and ASD with large total cerebral volumes (LTCV) compared to TD controls (n=20). Results: A total of 53 genes were predicted to have DAS for ALL ASD versus TD, 169 genes for ASD_NTCV versus TD, 1 gene for ASD_LTCV versus TD, and 27 genes for ASD_LTCV versus ASD_NTCV. These differences were significant at P <0.05 after false discovery rate corrections for multiple comparisons (FDR <5% false positives). A number of the genes predicted to have DAS in ASD are known to regulate DAS (SFPQ, SRPK1, SRSF11, SRSF2IP, FUS, LSM14A). In addition, a number of genes with predicted DAS are involved in pathways implicated in previous ASD studies, such as ROS monocyte/macrophage, Natural Killer Cell, mTOR, and NGF signaling.
    [Show full text]
  • GLI3 Knockdown Decreases Stemness, Cell Proliferation and Invasion in Oral Squamous Cell Carcinoma
    2458 INTERNATIONAL JOURNAL OF ONCOLOGY 53: 2458-2472, 2018 GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma MARIA FERNANDA SETÚBAL DESTRO RODRIGUES1,2, LUCYENE MIGUITA2, NATHÁLIA PAIVA DE ANDRADE2, DANIELE HEGUEDUSCH2, CAMILA OLIVEIRA RODINI3, RAQUEL AJUB MOYSES4, TATIANA NATASHA TOPORCOV5, RICARDO RIBEIRO GAMA6, ELOIZA ELENA TAJARA7 and FABIO DAUMAS NUNES2 1Postgraduate Program in Biophotonics Applied to Health Sciences, Nove de Julho University (UNINOVE), São Paulo 01504000; 2Department of Oral Pathology, School of Dentistry, University of São Paulo, São Paulo 05508000; 3Department of Biological Sciences, Bauru School of Dentistry, Bauru 17012901; 4Department of Head and Neck Surgery, School of Medicine, 5School of Public Health, University of São Paulo, São Paulo 03178200; 6Department of Head and Neck Surgery, Barretos Cancer Hospital, Barretos 014784400; 7Department of Molecular Biology, School of Medicine of São José do Rio Preto, São José do Rio Preto 15090000, Brazil Received February 28, 2018; Accepted June 29, 2018 DOI: 10.3892/ijo.2018.4572 Abstract. Oral squamous cell carcinoma (OSCC) is an expression of the Involucrin (IVL) and S100A9 genes. Cellular extremely aggressive disease associated with a poor prognosis. proliferation and invasion were inhibited following GLI3 Previous studies have established that cancer stem cells (CSCs) knockdown. In OSCC samples, a high GLI3 expression was actively participate in OSCC development, progression and associated with tumour size but not with prognosis. On the resistance to conventional treatments. Furthermore, CSCs whole, the findings of this study demonstrate for the first time, frequently exhibit a deregulated expression of normal stem at least to the best of our knowledge, that GLI3 contributes cell signalling pathways, thereby acquiring their distinctive to OSCC stemness and malignant behaviour.
    [Show full text]
  • Tamoxifen Resistance: Emerging Molecular Targets
    International Journal of Molecular Sciences Review Tamoxifen Resistance: Emerging Molecular Targets Milena Rondón-Lagos 1,*,†, Victoria E. Villegas 2,3,*,†, Nelson Rangel 1,2,3, Magda Carolina Sánchez 2 and Peter G. Zaphiropoulos 4 1 Department of Medical Sciences, University of Turin, Turin 10126, Italy; [email protected] 2 Faculty of Natural Sciences and Mathematics, Universidad del Rosario, Bogotá 11001000, Colombia; [email protected] 3 Doctoral Program in Biomedical Sciences, Universidad del Rosario, Bogotá 11001000, Colombia 4 Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge 14183, Sweden; [email protected] * Correspondence: [email protected] (M.R.-L.); [email protected] (V.E.V.); Tel.: +39-01-1633-4127 (ext. 4388) (M.R.-L.); +57-1-297-0200 (ext. 4029) (V.E.V.); Fax: +39-01-1663-5267 (M.R.-L.); +57-1-297-0200 (V.E.V.) † These authors contributed equally to this work. Academic Editor: William Chi-shing Cho Received: 5 July 2016; Accepted: 16 August 2016; Published: 19 August 2016 Abstract: 17β-Estradiol (E2) plays a pivotal role in the development and progression of breast cancer. As a result, blockade of the E2 signal through either tamoxifen (TAM) or aromatase inhibitors is an important therapeutic strategy to treat or prevent estrogen receptor (ER) positive breast cancer. However, resistance to TAM is the major obstacle in endocrine therapy. This resistance occurs either de novo or is acquired after an initial beneficial response. The underlying mechanisms for TAM resistance are probably multifactorial and remain largely unknown. Considering that breast cancer is a very heterogeneous disease and patients respond differently to treatment, the molecular analysis of TAM’s biological activity could provide the necessary framework to understand the complex effects of this drug in target cells.
    [Show full text]
  • GLI2 but Not GLI1/GLI3 Plays a Central Role in the Induction of Malignant Phenotype of Gallbladder Cancer
    ONCOLOGY REPORTS 45: 997-1010, 2021 GLI2 but not GLI1/GLI3 plays a central role in the induction of malignant phenotype of gallbladder cancer SHU ICHIMIYA1, HIDEYA ONISHI1, SHINJIRO NAGAO1, SATOKO KOGA1, KUKIKO SAKIHAMA2, KAZUNORI NAKAYAMA1, AKIKO FUJIMURA3, YASUHIRO OYAMA4, AKIRA IMAIZUMI1, YOSHINAO ODA2 and MASAFUMI NAKAMURA4 Departments of 1Cancer Therapy and Research, 2Anatomical Pathology, 3Otorhinolaryngology and 4Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan Received August 10, 2020; Accepted December 7, 2020 DOI: 10.3892/or.2021.7947 Abstract. We previously reported that Hedgehog (Hh) signal Introduction was enhanced in gallbladder cancer (GBC) and was involved in the induction of malignant phenotype of GBC. In recent Gallbladder cancer (GBC) is the seventh most common gastro- years, therapeutics that target Hh signaling have focused on intestinal carcinoma and accounts for 1.2% of all cancer cases molecules downstream of smoothened (SMO). The three tran- and 1.7% of all cancer-related deaths (1). GBC develops from scription factors in the Hh signal pathway, glioma-associated metaplasia to dysplasia to carcinoma in situ and then to invasive oncogene homolog 1 (GLI1), GLI2, and GLI3, function down- carcinoma over 5‑15 years (2). During this time, GBC exhibits stream of SMO, but their biological role in GBC remains few characteristic symptoms, and numerous cases have already unclear. In the present study, the biological significance of developed into locally advanced or metastasized cancer by the GLI1, GLI2, and GLI3 were analyzed with the aim of devel- time of diagnosis. Gemcitabine (GEM), cisplatin (CDDP), and oping novel treatments for GBC.
    [Show full text]
  • COFACTORS of the P65- MEDIATOR COMPLEX
    COFACTORS OF THE April 5 p65- MEDIATOR 2011 COMPLEX Honors Thesis Department of Chemistry and Biochemistry NICHOLAS University of Colorado at Boulder VICTOR Faculty Advisor: Dylan Taatjes, PhD PARSONNET Committee Members: Rob Knight, PhD; Robert Poyton, PhD Table of Contents Abstract ......................................................................................................................................................... 3 Introduction .................................................................................................................................................. 4 The Mediator Complex ............................................................................................................................. 6 The NF-κB Transcription Factor ................................................................................................................ 8 Hypothesis............................................................................................................................................... 10 Results ......................................................................................................................................................... 11 Discussion.................................................................................................................................................... 15 p65-only factors ...................................................................................................................................... 16 p65-enriched factors ..............................................................................................................................
    [Show full text]
  • Emx2 Is Required for Growth of the Hippocampus but Not for Hippocampal Field Specification
    The Journal of Neuroscience, April 1, 2000, 20(7):2618–2625 Emx2 Is Required for Growth of the Hippocampus But Not for Hippocampal Field Specification Shubha Tole,1 Guy Goudreau,2 Stavroula Assimacopoulos,1 and Elizabeth A. Grove1 1Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois 60637, and 2Max Planck Institute of Biophysical Chemistry, D-37077 Goettingen, Germany The vertebrate Emx genes are expressed in a nested pattern in positioned in the Emx2 mutant. In particular, a dentate cell early embryonic cerebral cortex, such that a medial strip of population is generated, although it fails to form a morpholog- cortex expresses Emx2 but not Emx1. This pattern suggests ical gyrus. This failure may be part of a more widespread medial that Emx genes could play a role in specifying different areas or cortical defect in the mutant. Examination of cortical cell pro- fields of the cortex along the mediolateral axis. Such a role has liferation and differentiation indicates a disruption of the matu- been supported by the observation that in mice lacking func- ration of the medial cortex in the absence of Emx2. Thus, Emx2 tional Emx2 the hippocampus is shrunken and the most medial is required for normal growth and maturation of the hippocam- field of the cortex, the hippocampal dentate gyrus, appears by pus but not for the specification of cells to particular hippocam- cytoarchitecture to be missing (Pellegrini et al., 1996; Yoshida et pal field identities. al., 1997). Use of region-specific molecular markers shows, Key words: Emx2; hippocampus; patterning; specification; however, that hippocampal fields are specified and correctly cortical maturation; cortical hem The hippocampus, like the rest of the cerebral cortex, is divided Reports that specific mutations lead to morphological defects in into cytoarchitectonic areas or fields (Nauta and Feirtag, 1986).
    [Show full text]
  • MED12 Related Disorders FTNW
    MED12 related disorders rarechromo.org What are the MED12 related disorders? MED12 related disorders are a group of disorders that primarily affect boys. Most boys with MED12 related disorders have intellectual disability/ developmental delay, behavioural problems and low muscle tone. MED12 related disorders occur when the MED12 gene has lost its normal function. Genes are instructions which have important roles in our growth and development. They are made of DNA and are incorporated into organised structures called chromosomes. Chromosomes therefore contain our genetic information. Chromosomes are located in our cells, the building blocks of our bodies. The MED12 gene is located on the X chromosome. The X chromosome is one of the sex chromosomes that determine a person’s gender. Men have one X chromosome and one Y chromosome, while women have two X chromosomes. Because the MED12 gene is located on the X chromosome, men have only one copy of the gene, while women have two copies. A change in the MED12 gene can cause symptoms in men. Women with a change in the MED12 gene usually have no symptoms. They carry a second copy of the gene that does function normally. Women may show mild features such as learning difficulties. The MED12 related disorders are FG syndrome , Lujan syndrome and the X- linked recessive form of Ohdo syndrome . Although these syndromes differ, they also have the overlapping features listed on page 2. The way that these conditions are inherited is called ‘X-linked’ or ‘X-linked’ recessive. In 2007 it was discovered that changes in the MED12 gene were responsible for the symptoms and features in several boys with FG syndrome.
    [Show full text]
  • CIC Is a Critical Regulator of Neuronal Differentiation
    CIC is a critical regulator of neuronal differentiation Inah Hwang, … , Hongwu Zheng, Jihye Paik JCI Insight. 2020. https://doi.org/10.1172/jci.insight.135826. Research In-Press Preview Oncology Stem cells Capicua (CIC), a member of the high mobility group (HMG)-box superfamily of transcriptional repressors, is frequently mutated in human oligodendrogliomas. But its function in brain development and tumorigenesis remains poorly understood. Here, we report that brain-specific deletion of Cic compromises developmental transition of neuroblast to immature neurons in mouse hippocampus and compromises normal neuronal differentiation. Combined gene expression and ChIP-seq analyses identified VGF as an important CIC-repressed transcriptional surrogate involved in neuronal lineage regulation. Aberrant VGF expression promotes neural progenitor cell proliferation by suppressing their differentiation. Mechanistically, we demonstrated that CIC represses VGF expression by tethering SIN3-HDAC to form a transcriptional corepressor complex. Mass spectrometry analysis of CIC-interacting proteins further identified BRG1 containing mSWI/SNF complex whose function is necessary for transcriptional repression by CIC. Together, this study uncovers a novel regulatory pathway of CIC-dependent neuronal differentiation and may implicate these molecular mechanisms in CIC-dependent brain tumorigenesis. Find the latest version: https://jci.me/135826/pdf CIC is a Critical Regulator of Neuronal Differentiation Inah Hwang1,4, Heng Pan2,3,4, Jun Yao5, Olivier Elemento2,3,4, Hongwu Zheng1,4 and Jihye Paik1,4* 1Department of Pathology and Laboratory medicine. Weil Cornell Medicine, New York, NY10021, USA 2Department of Physiology and Biophysics, Weil Cornell Medicine, New York, NY10021, USA 3Caryl and Israel Englander Institute for Precision Medicine, NewYork-Presbyterian Hospital.
    [Show full text]