DOCSLIB.ORG

Cooperation to Amplify Gene-Dosage-Imbalance Effects

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Cooperation to Amplify Gene-Dosage-Imbalance Effects Update TRENDS in Molecular Medicine Vol.12 No.10 Research Focus Cooperation to amplify gene-dosage-imbalance effects Susana de la Luna1 and Xavier Estivill2 1 ICREA and Gene Function Group, Genes and Disease Program, Center for Genomic Regulation-CRG, 08003-Barcelona, Spain 2 Genetic Causes of Disease Group, Genes and Disease Program, Center for Genomic Regulation-CRG and Pompeu Fabra University, Barcelona Biomedical Research Park, 08003-Barcelona, Spain Trisomy 21, also known as Down syndrome (DS), is a From gene-dosage imbalance to pathology complex developmental disorder that affects many ThepresenceofanextracopyofHSA21 genes predicts an organs, including the brain, heart, skeleton and increased expression of 1.5-fold at the RNA level for immune system. A working hypothesis for understand- those genes in trisomy. Experiments in which this effect ing the consequences of trisomy 21 is that the over- has been evaluated indicate that this is indeed the case expression of certain genes on chromosome 21, alone for most HSA21 genes in DS samples and for their or in cooperation, is responsible for the clinical features orthologs in mouse trisomic models [3].Inthesimplest of DS. There is now compelling evidence that the scenario, the overexpression of one specific gene would protein products of two genes on chromosome 21, lead to the disturbance of a biological process and, as a Down syndrome candidate region 1 (DSCR1)and result, a single gene would be responsible for each patho- dual-specificity tyrosine-(Y)-phosphorylation regulated logical feature of DS. However, it is more probable that kinase 1A (DYRK1A), interact functionally, and that the overexpression of several of the 250 HSA21 genes their increased dosage cooperatively leads to dysregu- would contribute to alter a functional pathway in a lation of the signaling pathways that are controlled by specific cell at a specific time. In some cases, functional the nuclear factor of activated T cells (NFAT) family of interactions would result in additive or even synergistic transcription factors, with potential consequences for effects, leading to signal amplification. In others, the several organs and systems that are affected in DS positive effect of one gene might counteract the detri- individuals. mental effects of other dosage-sensitive genes that act on the same pathway and, hence, result in no net change. Whatever the case might be, the final phenotypic out- Trisomy 21 and Down syndrome: genotype and come cannot be foreseen on the basis of analyzing the phenotype overexpression of single genes. Humans have two copies of each of the 23 autosomic chromosomes in all their somatic cells. In some genetic A novel altered pathway in Down syndrome abnormalities that are known as trisomies, an extra A clear example of a cooperative interaction between chromosome is present due to defective chromosome two HSA21 genes on a signaling pathway has recently segregation during germ-cell meiosis. Trisomy of been presented for the nuclear factor of activated human chromosome 21 (HSA21)isthemostcommon T cells (NFAT) pathway (see Glossary), as the result of trisomy at birth, the only one for which individuals the collaborative effort of several groups at Stanford survive beyond childhood and the cause of a develop- University and the Genetic Engineering Unit at Kyoto mental and dysmorphic disorder known as Down syndrome University [4]. (DS). NFAT transcription factors are well-known regulators The clinical presentation of DS is complex because the of development and normal physiology in mammals [5]. normal physiology of many organs and systems is Their activity is controlled by cycles of dephosphorylation affected. Apart from the distinctive facial features, all and phosphorylation that determine the amount of the DS individuals present intellectual disabilities, hypoto- transcription factor in the nucleus and, therefore, the nia and early development of the pathological changes final transcriptional response [6]. The phosphatase that are typical of Alzheimer’s disease (AD). Other clin- calcineurin is responsible, following increases in intra- ical features not observed in all DS individuals include cellular Ca2+, for the NFAT dephosphorylation step heart defects, abnormalities of the gut and the immune and subsequent nuclear entry. Several kinases, including system, and increased risk of leukaemia, among many glycogen synthase 3 and casein kinase 1, participate in others [1,2]. The severity of each feature, including the phosphorylation step that acts as a switch-off mental retardation, is highly variable among indivi- mechanism [6]. duals, suggesting that there is an important contribution One HSA21 gene, Down syndrome candidate region 1 of other influences such as stochastic, environmental or (DSCR1), acts as a negative regulator of this pathway genetic factors. by virtue of its inhibitory activity on calcineurin [7]. Given the significant connection of calcineurin with Corresponding author: de la Luna, S. ([email protected]) disease, the DSCR1 gene has received a lot of attention, Available online 17 August 2006. and many names have been given to its protein www.sciencedirect.com 452 Update TRENDS in Molecular Medicine Vol.12 No.10 that were engineered not to express one or several NFAT Glossary family members or to lack calcineurin activity. The pre- Calcineurin (also known as protein phosphatase 2B): it is an enzyme that sence of DS-like phenotypes in these mice led the authors catalyzes the dephosphorylation of phosphorylated serine–threonine residues in proteins, and the only phosphatase that is regulated by Ca2+. Calcineurin is to conclude that reduced NFAT activity might be impli- involved in the regulation of many cellular processes, including cardiac cated in the appearance of cardiovascular, neurological, hypertrophy, skeletal-muscle development, synaptic plasticity and T-cell skeletal and gastrointestinal defects in DS individuals. activation. In this regard, calcineurin is the main target of the immunosup- pressive drugs cyclosporine A and FK506. The dysregulation of the NFAT pathway in DS had DSCR1: it belongs to a family of small and evolutionary conserved proteins that already been hinted at by the lower-than-normal calci- share the ability of binding to and inhibit calcineurin. In humans, the family neurin activity that has been detected in DS fetal brains consists of three members, DSCR1, DSCR1L1 and DSCR1L2, the expression of which is induced by different stimuli, including calcineurin activation in [9] and by the decreased activity of an NFAT-dependent the case of DSCR1. It has been proposed that the members of this family alter reporter in the heart and brain of the DS mouse the threshold for calcineurin signaling. For DSCR1, a cardioprotective role in model Ts16 [14]. In agreement with this, Arron et al. the heart has been reported. DYRK1A: it is a kinase that phosphorylates serine–threonine residues in [4] reported an increase in NFAT hyperphosphorylated proteins. DYRK1A belongs to the DYRK family, an evolutionarily conserved species in DS-tissue samples. Mechanistically, this is family of protein kinases, with members identified from yeast to humans, that explained by a cooperative effect of DSCR1 and DYRK1A participate in various cellular processes. The DYRK family is characterized by its activation mechanism that involves the autophosphorylation on a tyrosine on NFAT activity that, by negatively operating on residue in the activation loop. DYRK1A phosphorylates several cytosolic different steps of the signaling cascade, would amplify proteins and some splicing and transcription factors, including members of the NFAT family. the modest interference provoked by each protein alone Nuclear factor of activated T cells (NFAT): it is a family of transcription factors (Figure 1). with five members in humans. Their activity is mainly regulated by their However, some notes of caution need to be borne in subcellular localization, which depends on the phosphorylation status. They are well-known substrates of calcineurin, and one of the best examples to mind. show how Ca2+ signaling can control gene expression. NFATs, through the In the study by Arron et al. [4] DSCR1 and DYRK1A induction of the expression of specific genes, are key regulators of the cooperation in vivo is supported by the defects detected differentiation of various cell types (e.g. T cells, neurons, myoblasts, endothelial cells and adipocytes), and they thus participate in the appropriate in double transgenic embryos in which expression is development of several organs and systems. driven by the b-actin promoter. Overexpression from a heterologous promoter might not recapitulate the endogenous gene-expression pattern and, therefore, products:ADAPT78,MCIP1,RCN1,CBP1andcalcipres- coincidence in cell type and/or time period cannot be sin1.AHumanGenomeOrganization(HUGO)initiative assumed with certainty. to rename DSCR1 as RCAN1 (regulator of calcineurin 1) One of the isoforms of DSCR1 is itself under NFAT is underway. Dscr1 knockout mice are viable and present control. Thus, a negative effect of DYRK1A overexpres- phenotypes that link the gene to the regulation of sion on NFAT signaling might give rise to lowered calcineurin–NFAT-dependent transcription programs DSCR1 expression in a Ca2+-stimulated situation and [8]. However, no specific phenotypes associated to result in attenuation. DSCR1 overexpression and relevant for DS have been It has been reported that, when DSCR1 trisomy is reported, except for the Drosophila
Load more

Recommended publications
  • RCAN2 Isoform 2 Recombinant Protein Cat
    RCAN2 Isoform 2 Recombinant Protein Cat. No.: 95-114 RCAN2 Isoform 2 Recombinant Protein Specifications SPECIES: Mouse SOURCE SPECIES: E. coli SEQUENCE: aa 2 - 197 FUSION TAG: Fusion Partner: C-terminal His-tag TESTED APPLICATIONS: ELISA, WB APPLICATIONS: This recombinant protein can be used for WB and ELISA. For research use only. PREDICTED MOLECULAR 26 kDa (Calculated) WEIGHT: Properties PURITY: ~95% PHYSICAL STATE: Liquid 100mM sodium phosphate, 10mM Tris, 500mM NaCl, 25 mM imidazole, 2mM MgCl2, 10% BUFFER: gycerol Store in working aliquots at -70˚C. Avoid freeze/thaw cycles. When working with proteins STORAGE CONDITIONS: care should be taken to keep recombinant protein at a cool and stable temperature. September 29, 2021 1 https://www.prosci-inc.com/rcan2-isoform-2-recombinant-protein-95-114.html Additional Info OFFICIAL SYMBOL: Rcan2 RCAN2 Antibody: Csp2, MCIP2, ZAKI-4, Dscr1l1, Zaki4, Calcipressin-2, Calcineurin inhibitory ALTERNATE NAMES: protein ZAKI-4 ACCESSION NO.: AAH62141 PROTEIN GI NO.: 38328420 GENE ID: 53901 Background and References Regulator of calcineurin 2 (RCAN2), also known as ZAKI4 and DSCR1L1, is expressed as two isoforms differing at their N-terminus. The longer of the two (isoform 1) is expressed exclusively in the brain, while isoform 2 is ubiquitously expressed, with highest expression in brain, heart, and muscle (1,2). Both isoforms bind to the catalytic subunit of calcineurin, a Ca++-dependent protein phosphatase involved in several neuronal functions, though BACKGROUND: their C-terminal region and inhibit calcineurin’s activity (3). Unlike isoform 1 of RCAN2, the expression of the second isoform is not induced by the thyroid hormone T3 (3).
    [Show full text]
  • Regulator of Calcineurin (RCAN): Beyond Down
    Molecules and Cells Minireview Regulator of Calcineurin (RCAN): Beyond Down Syndrome Critical Region Sun-Kyung Lee1,2,* and Joohong Ahnn1,2,* 1Department of Life Science, 2Research Institute for Natural Sciences, College of Natural Sciences, Hanyang University, Seoul 04763, Korea *Correspondence: [email protected] (SKL); [email protected] (JA) https://doi.org/10.14348/molcells.2020.0060 www.molcells.org The regulator of calcineurin (RCAN) was first reported as RCAN3 a novel gene called DSCR1, encoded in a region termed the Down syndrome critical region (DSCR) of human chromosome 21. Genome sequence comparisons across INTRODUCTION species using bioinformatics revealed three members of the RCAN gene family, RCAN1, RCAN2, and RCAN3, present in The regulator of calcineurin (RCAN) was first reported as a most jawed vertebrates, with one member observed in most Down syndrome critical region 1 (DSCR1), which is encoded invertebrates and fungi. RCAN is most highly expressed in in a region that at that time was thought to participate in the brain and striated muscles, but expression has been reported onset of Down syndrome (DS) (Antonarakis, 2017; Fuentes in many other tissues, as well, including the heart and et al., 1995). Soon after, evidence showed that RCAN binds kidneys. Expression levels of RCAN homologs are responsive to and regulates the Ca2+/calmodulin-dependent serine/thre- to external stressors such as reactive oxygen species, Ca2+, onine phosphatase calcineurin, whose substrates include nu- amyloid β, and hormonal changes and upregulated in clear factor of activated T cells (NFAT), the transcription factor pathological conditions, including Alzheimer’s disease, that regulates gene expression in many cell types, including cardiac hypertrophy, diabetes, and degenerative neuropathy.
    [Show full text]
  • The Genetic Architecture of Down Syndrome Phenotypes Revealed by High-Resolution Analysis of Human Segmental Trisomies
    The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies Jan O. Korbela,b,c,1, Tal Tirosh-Wagnerd,1, Alexander Eckehart Urbane,f,1, Xiao-Ning Chend, Maya Kasowskie, Li Daid, Fabian Grubertf, Chandra Erdmang, Michael C. Gaod, Ken Langeh,i, Eric M. Sobelh, Gillian M. Barlowd, Arthur S. Aylsworthj,k, Nancy J. Carpenterl, Robin Dawn Clarkm, Monika Y. Cohenn, Eric Dorano, Tzipora Falik-Zaccaip, Susan O. Lewinq, Ira T. Lotto, Barbara C. McGillivrayr, John B. Moeschlers, Mark J. Pettenatit, Siegfried M. Pueschelu, Kathleen W. Raoj,k,v, Lisa G. Shafferw, Mordechai Shohatx, Alexander J. Van Ripery, Dorothy Warburtonz,aa, Sherman Weissmanf, Mark B. Gersteina, Michael Snydera,e,2, and Julie R. Korenbergd,h,bb,2 Departments of aMolecular Biophysics and Biochemistry, eMolecular, Cellular, and Developmental Biology, and fGenetics, Yale University School of Medicine, New Haven, CT 06520; bEuropean Molecular Biology Laboratory, 69117 Heidelberg, Germany; cEuropean Molecular Biology Laboratory (EMBL) Outstation Hinxton, EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom; dMedical Genetics Institute, Cedars–Sinai Medical Center, Los Angeles, CA 90048; gDepartment of Statistics, Yale University, New Haven, CT 06520; Departments of hHuman Genetics, and iBiomathematics, University of California, Los Angeles, CA 90095; Departments of jPediatrics and kGenetics, University of North Carolina, Chapel Hill, NC 27599; lCenter for Genetic Testing,
    [Show full text]
  • DYRK1A and RCAN1
    BMB reports Mini Review Two key genes closely implicated with the neuropathological characteristics in Down syndrome: DYRK1A and RCAN1 Joongkyu Park#, Yohan Oh# & Kwang Chul Chung* Department of Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea The most common genetic disorder Down syndrome (DS) dis- 21) (2, 3). Other phenotypic features of DS include cognitive plays various developmental defects including mental re- impairment, learning and memory deficit, a high risk of leuke- tardation, learning and memory deficit, the early onset of mia, a decreased risk of solid tumors, congenital heart disease Alzheimer’s disease (AD), congenital heart disease, and cranio- and hypotonia (3-5). Moreover, DS brains show additional facial abnormalities. Those characteristics result from the ex- neuropathological outcomes such as the arrest of neurogenesis tra-genes located in the specific region called ‘Down syn- and synaptogenesis, and neuronal differentiation defects (6, 7). drome critical region (DSCR)’ in human chromosome 21. In They also exhibit a lower brain weight with reduced neuronal this review, we summarized the recent findings of the density, number, and volume regardless of region and age (6, DYRK1A and RCAN1 genes, which are located on DSCR and 8, 9). Although the cause of these CNS hypoplasias in DS pa- thought to be closely associated with the typical features of DS tients remains unclear, several reports using DS brains and cul- patients, and their implication to the pathogenesis of neural tured DS fibroblasts suggest that it may result from enhanced defects in DS. DYRK1A phosphorylates several transcriptional cell death and impaired cell proliferation (6, 7, 10, 11).
    [Show full text]
  • GSK-3 Kinases Enhance Calcineurin Signaling by Phosphorylation of Rcns
    Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press GSK-3 kinases enhance calcineurin signaling by phosphorylation of RCNs Zoe Hilioti,1 Deirdre A. Gallagher,1 Shalini T. Low-Nam,1 Priya Ramaswamy,1 Pawel Gajer,1 Tami J. Kingsbury,1 Christine J. Birchwood,1 Andre Levchenko,2 andKyle W. Cunningham 1,3 1Department of Biology and 2Whitaker Institute for Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland 21218, USA The conservedRCN family of proteins can bindanddirectlyregulate calcin eurin, a Ca2+-activatedprotein phosphatase involvedin immunity, heart growth, muscle development,learning, andother processes. Whereas high levels of RCNs can inhibit calcineurin signaling in fungal andanimal cells, RCNs can also stimulate calcineurin signaling when expressedat endogenouslevels. Here we show t hat the stimulatory effect of yeast Rcn1 involves phosphorylation of a conservedserine residueby Mck1, a mem ber of the GSK-3 family of protein kinases. Mutations at the GSK-3 consensus site of Rcn1 andhuman DS CR1/MCIP1 abolish the stimulatory effects on calcineurin signaling. RCNs may therefore oscillate between stimulatory andinhibitory forms in vivo in a manner similar to the Inhibitor-2 regulators of type 1 protein phosphatase. Computational modeling indicates a biphasic response of calcineurin to increasing RCN concentration such that protein phosphatase activity is stimulatedby low concentrations of phospho-RCN andinhibitedby high concentrations of phospho- or dephospho-RCN. This prediction was verifiedexperimentally in yeast cells expressing Rcn1 or DSCR1/MCIP1 at different concentrations. Through the phosphorylation of RCNs, GSK-3 kinases can potentially contribute to a positive feedback loop involving calcineurin-dependent up-regulation of RCN expression.
    [Show full text]
  • Epigenetic Modulations Induction Using DSCR1 Ectopic Expression in Breast Cancer Cells
    Copyright © 2019 Tech Science Press MCB, vol.16, no.1, pp.41-58, 2019 Epigenetic Modulations Induction Using DSCR1 Ectopic Expression in Breast Cancer Cells Zahra Niki Boroujeni1, Atefeh Shirkavand1 and Seyed Ahmad Aleyasin1, * Abstract: Today, prognosis, diagnosis and treatment of cancers are progressing with non-invasive methods, including investigation and modification of the DNA methylation profile in cancer cells. One of the effective factors in regulating gene expression in mammals is DNA methylation. Methylation alterations of genes by external factors can change the expression of genes and inhibit the cancer. In the present study, we investigated the effect of Down syndrome critical region 1 gene (DSCR1) ectopic expression on the methylation status of the BCL-XL, ITGA6, TCF3, RASSF1A, DOK7, VIM and CXCR4 genes in breast cancer cell lines. The effect of DSCR1 ectopic expression on cell viability in MCF7, MDA-MB-468, MDA-MB-231 and MCF10A cell lines was evaluated using MTT assay after the cells treated by lentivirus vectors harboring DSCR1 for 72 hours. Methylation status of BCL-XL, ITGA6, TCF3, RASSF1A, DOK7, VIM and CXCR4 genes in breast cancer cell lines was assessed by Restriction Enzyme PCR (REP) method. Also, methylation changes of these genes in breast cancer cell lines after treatment by lentivirus vectors harboring DSCR1 for 7 days were analyzed by REP method. To confirm the effect of DSCR1 on methylation of genes, Real-time PCR was performed. The MTT assay results indicated that DSCR1 ectopic expression reduced cell viability in all three human breast cancer cell lines. Our results showed that DSCR1 ectopic expression after 6 days reversed the hypomethylation status of the BCL- XL, ITGA6, TCF3, VIM and CXCR4 genes and hypermethylation of RASSF1A and DOK7 genes.
    [Show full text]
  • Human RCAN3 Gene Expression and Cell Growth in Endothelial Cells
    913-918.qxd 19/10/2010 09:34 Ì ™ÂÏ›‰·913 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 26: 913-918, 2010 913 Human RCAN3 gene expression and cell growth in endothelial cells SILVIA CANAIDER1, MARINA VETTRAINO1, LUCY V. NORLING2, ENZO SPISNI3, FEDERICA FACCHIN1, DIANNE COOPER2 and MAURO PERRETTI2 1Department of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, Bologna, Italy; 2William Harvey Research Institute, Queen Mary University of London, Bart's and The London Medical School, Charterhouse Square, London, EC1M 6BQ, UK; 3Department of Experimental Biology, University of Bologna, via Selmi 3, 40126 Bologna, Italy Received May 28, 2010; Accepted July 20, 2010 DOI: 10.3892/ijmm_00000542 Abstract. Regulator of calcineurin 3 (RCAN3) belongs to the recent paper (5) will be used here. The human RCAN3 gene human RCAN gene family, which also includes RCAN1 and (1p36.11) encodes for a 241 amino acid predicted protein RCAN2. All three members interact with and inhibit calci- (27.5 kDa), is expressed in many human tissues (1,5) and is neurin. Based on this effect, several studies have demonstrated the most recent member of the human RCAN gene family, a role for RCAN1 and RCAN2 on inflammation, using human appearing only in vertebrates (6). RCAN-like proteins are umbilical vein endothelial cells (HUVECs) as a model. conserved from yeast to humans and share a highly conserved RCAN1 and 2 are strongly induced by vascular endothelial consensus motif (FLISPP motif) comprising the signature of growth factor (VEGF), inhibit cell proliferation and down- the family (1). RCAN3 has recently been demonstrated to regulate many pro-inflammatory and pro-angiogenic genes.
    [Show full text]
  • Ectopic Expression of DSCR1 in Conjunction with NDV Infection Reduces VEGF and Induces Apoptosis in Lung Cancer A549 Cell Line
    cer Scien an ce C & f o T l h Rad et al., J Cancer Sci Ther 2019, 11:1 a e n r a Journal of r p u DOI: 10.4172/1948-5956.1000574 y o J ISSN: 1948-5956 Cancer Science & Therapy Research Article Open Access Ectopic Expression of DSCR1 in Conjunction with NDV Infection Reduces VEGF and Induces Apoptosis in Lung Cancer A549 Cell Line Hanie Motahary Rad, Zahra Niki Boroujeni and Ahmad Aleyasin* Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran Abstract Lung cancer is one the most cause of cancer related deaths in the world. Newcastle Disease Virus (NDV) is an oncolytic and targeted self-amplifying agent that is able to replicates and kills only cancer cells. The strongest limitation of NDV in cancer treatments is due to its angiogenesis effect for tumors formation. The NDV mechanism for angiogenesis has not been described. This study was to evaluate for the first time the anti-angiogenesis effect of DSCR1 lonely and in conjunction with NDV in lung cancer cells. Ectopic expression of DSCR1 was induced by lentiviral transfection to A549 cell line. Transfected A549 was treated with the effective dose of NDV. Total RNA was extracted and cDNA was synthesized to detect DSCR1, VEGF, PCNA, Bax, and Bcl2 genes expressions compare to HPRT expression as a housekeeping gene using SYBR green Real-time PCR assay. Over expression of VEGF was detected in RNA level for the first time in NDV treated cells. Significant fold changes of PCNA, Bax, and Bcl2 showed that NDV used mitochondrial pathway for induction of cell death.
    [Show full text]
  • National Institutes of Health Research Plan on Down Syndrome
    A revised plan was published in 2014; this archived document is provided for reference only. National Institutes of Health Research Plan on Down Syndrome October 2007 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES (HHS) National Institutes of Health (NIH) Plan Developed by the NIH Down Syndrome Working Group A revised plan was published in 2014; this archived document is provided for reference only. A revised plan was published in 2014; this archived document is provided for reference only. TABLE OF CONTENTS EXECUTIVE SUMMARY .......................................................................................................... 1 SELECTED NIH RESEARCH OBJECTIVES ...................................................................................... 1 INTRODUCTION AND BACKGROUND................................................................................. 2 BACKGROUND ON DOWN SYNDROME .......................................................................................... 2 HIGHLIGHTS OF ONGOING RESEARCH ON DOWN SYNDROME AT THE NIH...... 3 NATIONAL CANCER INSTITUTE (NCI).......................................................................................... 3 NATIONAL HEART, LUNG, AND BLOOD INSTITUTE (NHLBI)....................................................... 4 NATIONAL INSTITUTE ON AGING (NIA)....................................................................................... 5 NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES (NIAID) ................................... 6 NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
    [Show full text]
  • Down Syndrome and Vascular Disease: DSCR1 and NFAT Signaling
    7 Down Syndrome and Vascular Disease: DSCR1 and NFAT Signaling Monica Y. Lee and Brian R. Wamhoff University of Virginia, Robert M. Berne Cardiovascular Research Center U.S.A. 1. Introduction Down Syndrome (DS) is one of the most common genetic disorders to date, occurring in 1 out of every 800-1000 live births (Egan et al. 2004; Roizen & Patterson, 2003; Stoll et al. 1990). DS patients often display several developmental and cognitive deficiencies. Common phenotypes of DS patients include congenital heart disease, dysmorphic physical features, and early-onset Alzheimer’s disease (AD). Since the discovery in 1959 that DS occurs from an extra copy of human chromosome 21 (hChr21) (Lejeune J, Gautier & Turpin, 1959), questions arose whether a 1.5-fold increase in a gene or set of genes were responsible for the phenotypes associated with DS. Sequence analysis of hChr21 indentified over 225 genes and/or predicted genes (Hattori et al. 2000). With the recent advances in sequencing, the gene content of hChr21 is now estimated to exceed 300 genes (Roizen & Patterson, 2003). While typically characterized by complete trisomy of hChr21, several DS cases, however, demonstrate that partial trisomy of hChr21 is enough to elicit the phenotypes associated with DS (Stoll et al. 1990), hence arising the concept of a Down Syndrome Critical Region (DSCR). The DSCR theory suggests that enhanced expression of a few genes located in this critical chromosomal region (between markers D21S17 and D21S55 (Delabar et al. 1993; Korenberg et al. 1994)) are responsible for some, if not all, of the features of DS. Olson LE et al show, however, that triplication of this region alone is not enough to fully manifest the phenotypes associated with DS (Olson et al.
    [Show full text]
  • Increased Dosage of DYRK1A and DSCR1 Delays Neuronal Differentiation in Neocortical Progenitor Cells
    Downloaded from genesdev.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Increased dosage of DYRK1A and DSCR1 delays neuronal differentiation in neocortical progenitor cells 1 Nobuhiro Kurabayashi and Kamon Sanada Molecular Genetics Research Laboratory, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan Down’s syndrome (DS), a major genetic cause of mental retardation, arises from triplication of genes on human chromosome 21. Here we show that DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) and DSCR1 (DS critical region 1), two genes lying within human chromosome 21 and encoding for a serine/ threonine kinase and calcineurin regulator, respectively, are expressed in neural progenitors in the mouse developing neocortex. Increasing the dosage of both proteins in neural progenitors leads to a delay in neuronal differentiation, resulting ultimately in alteration of their laminar fate. This defect is mediated by the cooperative actions of DYRK1A and DSCR1 in suppressing the activity of the transcription factor NFATc. In Ts1Cje mice, a DS mouse model, dysregulation of NFATc in conjunction with increased levels of DYRK1A and DSCR1 was observed. Furthermore, counteracting the dysregulated pathway ameliorates the delayed neuronal differentiation observed in Ts1Cje mice. In sum, our findings suggest that dosage of DYRK1A and DSCR1 is critical for proper neurogenesis through NFATc and provide a potential mechanism to explain the neurodevelopmental defects in DS. [Keywords: Down’s syndrome; developing neocortex; neurogenesis; neural progenitor] Supplemental material is available for this article. Received July 15, 2013; revised version accepted November 7, 2013. Down’s syndrome (DS), which occurs in one in 700–800 including neurological phenotypes (McCormick et al.
    [Show full text]
  • A Conserved Family of Calcineurin Regulators
    Downloaded from genesdev.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press A conserved family of calcineurin regulators Tami J. Kingsbury and Kyle W. Cunningham1 Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218 USA The protein phosphatase calcineurin mediates many cellular responses to calcium signals. Using a genetic screen in yeast, we identified a new family of proteins conserved in fungi and animals that inhibit calcineurin function when overexpressed. Overexpression of the yeast protein Rcn1p or the human homologs DSCR1 or ZAKI-4 inhibited two independent functions of calcineurin in yeast: The activation of the transcription factor Tcn1p and the inhibition of the H+/Ca2+ exchanger Vcx1p. Purified recombinant Rcn1p and DSCR1 bound calcineurin in vitro and inhibited its protein phosphatase activity. Signaling via calmodulin, calcineurin, and Tcn1p induced Rcn1p expression, suggesting that Rcn1p operates as an endogenous feedback inhibitor of calcineurin. Surprisingly, rcn1 null mutants exhibited phenotypes similar to those of Rcn1p-overexpressing cells. This effect may be due to lower expression of calcineurin in rcn1 mutants during signaling conditions. Thus, Rcn1p levels may fine-tune calcineurin signaling in yeast. The structural and functional conservation between Rcn1p and DSCR1 suggests that the mammalian Rcn1p-related proteins, termed calcipressins, will modulate calcineurin signaling in humans and potentially contribute to disorders such as Down Syndrome. [Key Words: Calcineurin; calcium signaling; Rcn1p; DSCR1; ZAKI-4] Received February 21, 2000; revised version accepted May 18, 2000. The calcium and calmodulin-activated protein phospha- 1997; Mendizabal et al. 1998; Stathopoulos-Gerontides tase calcineurin regulates a variety of developmental and et al.
    [Show full text]