DOCSLIB.ORG

Islet1 Deletion Causes Kidney Agenesis and Hydroureter Resembling CAKUT

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Islet1 Deletion Causes Kidney Agenesis and Hydroureter Resembling CAKUT BASIC RESEARCH www.jasn.org Islet1 Deletion Causes Kidney Agenesis and Hydroureter Resembling CAKUT † ‡ Yusuke Kaku,* Tomoko Ohmori,* Kuniko Kudo,* Sayoko Fujimura, Kentaro Suzuki, | Sylvia M. Evans,§ Yasuhiko Kawakami, and Ryuichi Nishinakamura* *Department of Kidney Development and †Liaison Laboratory Promotion Facility, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan; ‡Department of Developmental Genetics Research, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan; §Skaggs School of Pharmacy and Department of Medicine, University of California, San Diego, La Jolla, California; and |Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota ABSTRACT Islet1 (Isl1) is a transcription factor transiently expressed in a subset of heart and limb progenitors. During studies of limb development, conditional Isl1 deletion produced unexpected kidney abnormalities. Here, we studied the renal expression of Isl1 and whether it has a role in kidney development. In situ hybridiza- tion revealed Isl1 expression in the mesenchymal cells surrounding the base of the ureteric bud in mice. Conditional deletion of Isl1 caused kidney agenesis or hypoplasia and hydroureter, a phenotype resem- bling human congenital anomalies of the kidney and urinary tract (CAKUT). The absence of Isl1 led to ectopic branching of the ureteric bud out from the nephric duct or to the formation of accessory buds, both of which could lead to obstruction of the ureter-bladder junction and consequent hydroureter. The ab- normal elongation and poor branching of the ureteric buds were the likely causes of the kidney agenesis or hypoplasia. Furthermore, the lack of Isl1 reduced the expression of Bmp4, a gene implicated in the CAKUT-like phenotype, in the metanephric region before ureteric budding. In conclusion, Isl1 is essential for proper development of the kidney and ureter by repressing the aberrant formation of the ureteric bud. These observations call for further studies to investigate whether Isl1 may be a causative gene for human CAKUT. J Am Soc Nephrol 24: 1242–1249, 2013. doi: 10.1681/ASN.2012050528 The mammalian kidney, the metanephros, is mechanical obstruction of the ureter or malforma- formed by reciprocally inductive interactions be- tion of the smooth muscle layer causes dilatation of tween two precursor tissues: the metanephric mes- the ureter (hydroureter) and, in more severe cases, enchyme and the ureteric bud. The metanephric of the renal pelvis (hydronephrosis). The combi- mesenchyme attracts the ureteric bud tips toward nation of kidney and ureter defects caused by the mesenchyme and subsequently induces branch- gene mutations is termed congenital anomalies ing of the ureteric buds. The attracted ureteric bud of the kidney and urinary tract (CAKUT) and tips in turn induce the mesenchymal cells to differentiate into the epithelia of the glomeruli and renal tubules. Impairment of these processes Received May 28, 2012. Accepted March 24, 2013. can lead to a variety of abnormal developmental Y.K. and T.O. contributed equally to this work. disorders of the kidney. Meanwhile, the stalks of the Published online ahead of print. Publication date available at ureteric buds elongate and differentiate into col- www.jasn.org. lecting ducts and the ureter. The ureteric epithelium Correspondence: Prof. Ryuichi Nishinakamura, Department of also interacts with the surrounding ureteral mes- Kidney Development, Institute of Molecular Embryology and enchyme, which differentiates into the smooth Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto 860- muscle layer of the ureter that pushes the urine 0811, Japan. Email: [email protected] downward by peristaltic movements. Therefore, Copyright © 2013 by the American Society of Nephrology 1242 ISSN : 1046-6673/2408-1242 JAmSocNephrol24: 1242–1249, 2013 www.jasn.org BASIC RESEARCH constitutesa majorcause ofrenalfailure in the perinatalperiod in humans.1 Bmp4 is expressed in the mesenchyme surrounding the ureteric stalk, and Bmp4 heterozygous mutant mice display abnormalities that mimic human CAKUT, including hypo- plastic kidneys and hydroureter.2 These mice exhibit ectopic or accessory ureteric bud formation, which results in miscon- nection of the ureter to the urinary bladder or duplicated ure- ters. It has been proposed that Bmp4 has dual functions, namely inhibition of ectopic budding of the ureteric tips and promotion of ureteric stalk elongation,2 although the pre- cise mechanisms remain unknown. Shh is expressed in the ureteric epithelium, and its deletion results in reduced expres- sion of Bmp4 in the surrounding mesenchyme and eventually hydroureter.3 The transcription factors Tbx18 and Sox9 are expressed in the ureteric mesenchyme, and their deletion also leads to hydroureter resulting from impaired develop- ment of the smooth muscle layer of the ureter.4,5 In this study, we identify Islet1 (Isl1; Mouse Genome In- formatics), which encodes an LIM-homeodomain protein, as a key regulator of kidney and ureter development. Mice deficient for Isl1 die by embryonic day (E) 11.5 and exhibit developmental arrest of motor neurons.6 Isl1 is transiently ex- pressed in a subset of heart and limb progenitors and is re- quired for the normal development of these tissues.7,8 In the course of conditional Isl1 deletion in the lateral mesoderm using Hoxb6Cre for analysis of limb development,9 kidney abnormalities were observed. This finding was unexpected because no previous literature has reported Isl1 expression in the developing kidney to the best of our knowledge. There- fore, we examined the expression and roles of Isl1 in kidney development in detail. Figure 1. Isl1 is transiently expressed in the mesenchyme sur- rounding the kidney primordia. (A–D) In situ hybridization of Isl1 RESULTS during kidney development. Note that Isl1 is expressed in the mesenchyme surrounding the ureteric buds until E11.5 but rap- Isl1 Is Transiently Expressed in the Mesenchyme idly decreases thereafter. The signal at E14.5 is absent except for Surrounding the Ureteric Bud Stalk the preaortic sympathetic ganglia (*). (E) Whole-mount in situ First, we examined the expression patterns of Isl1 during kid- hybridization of Isl1 in the E14.5 kidney. (F–H) Immunostaining for Hoxb6Cre ney development by in situ hybridization. At E10.5, Isl1 was Isl1 using an anti-Isl1 antibody. (I and J) Cre activity in Hoxb6Cre;tdTomato expressed in tissues surrounding the cloaca but was excluded mice. Sections of reporter mice were stained with an anti-RFP antibody. Note the significant overlap of from the kidney primordia, comprising the metanephric mes- Isl1 and Hobx6Cre expression. Black arrowheads, ureteric bud enchyme and nephric duct (Figure 1A). At E11.5, a similar stalk; white arrowheads, ureter; cl, cloaca; im, intermediate me- Isl1 expression pattern was observed, in that expression was soderm; kid, kidney; lpm, lateral plate mesoderm; mm, meta- detected in the ureteric mesenchyme surrounding the ureteric nephric mesenchyme; nd, nephric duct. Scale bars: 100 mm. bud stalk and cloaca but was not expressed in the metanephric mesenchyme or ureteric bud epithelia (Figure 1B). Subse- quently, Isl1 expression was rapidly downregulated at E12.5 weakly in the lateral and intermediate mesoderm at E9.5 (Figure 1C), and no Isl1 expression was observed in the kid- and robustly in the ureteric mesenchyme at E11.5. (Figure 1, ney proper or the ureter at E14.5 (Figure 1D). These obser- G and H). vations were confirmed by whole-mount in situ hybridiza- Next, the Cre recombinase activity of Hoxb6Cre mice was tion, showing no Isl1 signals in the kidney or ureter at E14.5 examined. This mouse strain is often used for deletion of genes (Figure 1E). Staining with an anti-Isl1 antibody confirmed in lateral mesoderm-derived tissues, such as the limb buds.10 these observations, including the negative expression in the To examine the Cre activity in the developing kidney, ureter at E14.5 (Figure 1F). Nuclear Isl1 staining was observed we crossed Hoxb6Cre mice with a reporter strain, in which J Am Soc Nephrol 24: 1242–1249, 2013 Isl1 Knockout Causes CAKUT 1243 BASIC RESEARCH www.jasn.org the CAG promoter, stop sequences flanked by loxP sites, and the tandem dimer Tomato (tdTomato) are inserted into the Rosa26 locus.11 Owing to the presence of the potent CAG pro- moter, this mouse strain serves as a very sensitive reporter for Cre recombinase activity. When these mice were crossed with Hoxb6Cre mice, the tdTomato signals were detected mainly in the lateral mesoderm and weakly in the intermediate meso- derm at E9.5 (Figure 1I), which is consistent with the reported Cre activity.10 At E11.5, Cre activity was broadly detected, except for the ureteric bud epithelia (Figure 1J). Although the activity in the metanephric mesenchyme was mosaic, the regions with Cre activity cover all the Isl1-positive populations described above. Thus Hoxb6Cre mice are useful for efficient deletion of Isl1 during kidney development. The non-nuclear signal in the ureteric epithelium in Figure 1H, which is not consistent with the data obtained by in situ hybridization, could result from background staining of the antibody. In addition, the cryptic Isl1 expression in the ureteric epithelium does not affect our analysis because Hobx6Cre does not delete genes in this population. Isl1 Deletion Causes Kidney Agenesis or Hydroureter: A CAKUT-Like Phenotype flox/flox All the Hoxb6Cre;Isl1 mice died shortly after birth flox/flox flox/+ flox/+ Figure 2. Isl1 deletion causes kidney agenesis or hydroureter: (n=11), while Isl1 , Isl1 ,andHoxb6Cre;Isl1 flox/flox a CAKUT-like phenotype. (A) Kidneys in a newborn Isl1 mice were apparently normal (n=9, n=13, and n=21, respec- mouse (P0). ad, adrenal gland; bl, bladder; kid, kidney; ov, ovary. flox/flox tively). Regarding the 22 presumptive urogenital systems in (B) Bilateral kidney agenesis in a Hoxb6Cre;Isl1 mouse (P0). Hoxb6Cre;Isl1flox/flox the 11 mutant mice, 11 (50%) showed (C) Unilateral kidney agenesis accompanied by hydroureter (*) flox/flox complete kidney agenesis (Figure 2, A and B), 10 (45.5%) and hydronephrosis (**) in a Hoxb6Cre;Isl1 mouse (P0).
Load more

Recommended publications
  • Ncomms2254.Pdf
    ARTICLE Received 3 May 2012 | Accepted 5 Nov 2012 | Published 4 Dec 2012 DOI: 10.1038/ncomms2254 The RB family is required for the self-renewal and survival of human embryonic stem cells Jamie F. Conklin1,2,3, Julie Baker2,3 & Julien Sage1,2,3 The mechanisms ensuring the long-term self-renewal of human embryonic stem cells are still only partly understood, limiting their use in cellular therapies. Here we found that increased activity of the RB cell cycle inhibitor in human embryonic stem cells induces cell cycle arrest, differentiation and cell death. Conversely, inactivation of the entire RB family (RB, p107 and p130) in human embryonic stem cells triggers G2/M arrest and cell death through functional activation of the p53 pathway and the cell cycle inhibitor p21. Differences in E2F target gene activation upon loss of RB family function between human embryonic stem cells, mouse embryonic stem cells and human fibroblasts underscore key differences in the cell cycle regulatory networks of human embryonic stem cells. Finally, loss of RB family function pro- motes genomic instability in both human and mouse embryonic stem cells, uncoupling cell cycle defects from chromosomal instability. These experiments indicate that a homeostatic level of RB activity is essential for the self-renewal and the survival of human embryonic stem cells. 1 Department of Pediatrics, Stanford Medical School, Stanford, California 94305, USA. 2 Department of Genetics, Stanford Medical School, Stanford, California 94305, USA. 3 Institute for Stem Cell Biology and Regenerative Medicine, Stanford Medical School, Stanford, California 94305, USA. Correspondence and requests for materials should be addressed to J.S.
    [Show full text]
  • Prospective Isolation of NKX2-1–Expressing Human Lung Progenitors Derived from Pluripotent Stem Cells
    The Journal of Clinical Investigation RESEARCH ARTICLE Prospective isolation of NKX2-1–expressing human lung progenitors derived from pluripotent stem cells Finn Hawkins,1,2 Philipp Kramer,3 Anjali Jacob,1,2 Ian Driver,4 Dylan C. Thomas,1 Katherine B. McCauley,1,2 Nicholas Skvir,1 Ana M. Crane,3 Anita A. Kurmann,1,5 Anthony N. Hollenberg,5 Sinead Nguyen,1 Brandon G. Wong,6 Ahmad S. Khalil,6,7 Sarah X.L. Huang,3,8 Susan Guttentag,9 Jason R. Rock,4 John M. Shannon,10 Brian R. Davis,3 and Darrell N. Kotton1,2 2 1Center for Regenerative Medicine, and The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA. 3Center for Stem Cell and Regenerative Medicine, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas, USA. 4Department of Anatomy, UCSF, San Francisco, California, USA. 5Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA. 6Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, Massachusetts, USA. 7Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA. 8Columbia Center for Translational Immunology & Columbia Center for Human Development, Columbia University Medical Center, New York, New York, USA. 9Department of Pediatrics, Monroe Carell Jr. Children’s Hospital, Vanderbilt University, Nashville, Tennessee, USA. 10Division of Pulmonary Biology, Cincinnati Children’s Hospital, Cincinnati, Ohio, USA. It has been postulated that during human fetal development, all cells of the lung epithelium derive from embryonic, endodermal, NK2 homeobox 1–expressing (NKX2-1+) precursor cells.
    [Show full text]
  • Table S1 the Four Gene Sets Derived from Gene Expression Profiles of Escs and Differentiated Cells
    Table S1 The four gene sets derived from gene expression profiles of ESCs and differentiated cells Uniform High Uniform Low ES Up ES Down EntrezID GeneSymbol EntrezID GeneSymbol EntrezID GeneSymbol EntrezID GeneSymbol 269261 Rpl12 11354 Abpa 68239 Krt42 15132 Hbb-bh1 67891 Rpl4 11537 Cfd 26380 Esrrb 15126 Hba-x 55949 Eef1b2 11698 Ambn 73703 Dppa2 15111 Hand2 18148 Npm1 11730 Ang3 67374 Jam2 65255 Asb4 67427 Rps20 11731 Ang2 22702 Zfp42 17292 Mesp1 15481 Hspa8 11807 Apoa2 58865 Tdh 19737 Rgs5 100041686 LOC100041686 11814 Apoc3 26388 Ifi202b 225518 Prdm6 11983 Atpif1 11945 Atp4b 11614 Nr0b1 20378 Frzb 19241 Tmsb4x 12007 Azgp1 76815 Calcoco2 12767 Cxcr4 20116 Rps8 12044 Bcl2a1a 219132 D14Ertd668e 103889 Hoxb2 20103 Rps5 12047 Bcl2a1d 381411 Gm1967 17701 Msx1 14694 Gnb2l1 12049 Bcl2l10 20899 Stra8 23796 Aplnr 19941 Rpl26 12096 Bglap1 78625 1700061G19Rik 12627 Cfc1 12070 Ngfrap1 12097 Bglap2 21816 Tgm1 12622 Cer1 19989 Rpl7 12267 C3ar1 67405 Nts 21385 Tbx2 19896 Rpl10a 12279 C9 435337 EG435337 56720 Tdo2 20044 Rps14 12391 Cav3 545913 Zscan4d 16869 Lhx1 19175 Psmb6 12409 Cbr2 244448 Triml1 22253 Unc5c 22627 Ywhae 12477 Ctla4 69134 2200001I15Rik 14174 Fgf3 19951 Rpl32 12523 Cd84 66065 Hsd17b14 16542 Kdr 66152 1110020P15Rik 12524 Cd86 81879 Tcfcp2l1 15122 Hba-a1 66489 Rpl35 12640 Cga 17907 Mylpf 15414 Hoxb6 15519 Hsp90aa1 12642 Ch25h 26424 Nr5a2 210530 Leprel1 66483 Rpl36al 12655 Chi3l3 83560 Tex14 12338 Capn6 27370 Rps26 12796 Camp 17450 Morc1 20671 Sox17 66576 Uqcrh 12869 Cox8b 79455 Pdcl2 20613 Snai1 22154 Tubb5 12959 Cryba4 231821 Centa1 17897
    [Show full text]
  • Expression of the Human PAC1 Receptor Leads to Dose- Dependent Hydrocephalus-Related Abnormalities in Mice
    Expression of the human PAC1 receptor leads to dose- dependent hydrocephalus-related abnormalities in mice Bing Lang, … , Anthony J. Harmar, Sanbing Shen J Clin Invest. 2006;116(7):1924-1934. https://doi.org/10.1172/JCI27597. Research Article Neuroscience Hydrocephalus is a common and potentially devastating birth defect affecting the CNS, and its relationship with G protein–coupled receptors (GPCRs) is unknown. We have expressed 2, 4, or 6 copies of a GPCR — the human PAC1 receptor with a 130-kb transgene in the mouse nervous system in a pattern closely resembling that of the endogenous gene. Consistent with PAC1 actions, PKA and PKC activity were elevated in the brains of Tg mice. Remarkably, Tg mice developed dose-dependent hydrocephalus-like characteristics, including enlarged third and lateral ventricles and reduced cerebral cortex, corpus callosum, and subcommissural organ (SCO). Neuronal proliferation and apoptosis were implicated in hydrocephalus, and we observed significantly reduced neuronal proliferation and massively increased neuronal apoptosis in the developing cortex and SCO of Tg embryos, while neurite outgrowth and neuronal migration in vitro remain uncompromised. Ventricular ependymal cilia are crucial for directing cerebrospinal fluid flow, and ependyma of Tg mice exhibited disrupted cilia with increased phospho-CREB immunoreactivity. These data demonstrate that altered neuronal proliferation/apoptosis and disrupted ependymal cilia are the main factors contributing to hydrocephalus in PAC1-overexpressing mice. This is the first report to our knowledge demonstrating that misregulation of GPCRs can be involved in hydrocephalus-related neurodevelopmental disorders. Find the latest version: https://jci.me/27597/pdf Research article Related Commentary, page 1828 Expression of the human PAC1 receptor leads to dose-dependent hydrocephalus- related abnormalities in mice Bing Lang,1 Bing Song,1 Wendy Davidson,1 Alastair MacKenzie,1 Norman Smith,2 Colin D.
    [Show full text]
  • To Proliferate Or to Die: Role of Id3 in Cell Cycle Progression and Survival of Neural Crest Progenitors
    Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press To proliferate or to die: role of Id3 in cell cycle progression and survival of neural crest progenitors Yun Kee and Marianne Bronner-Fraser1 Division of Biology, California Institute of Technology, Pasadena, California 91125, USA The neural crest is a unique population of mitotically active, multipotent progenitors that arise at the vertebrate neural plate border. Here, we show that the helix–loop–helix transcriptional regulator Id3 has a novel role in cell cycle progression and survival of neural crest progenitors in Xenopus. Id3 is localized at the neural plate border during gastrulation and neurulation, overlapping the domain of neural crest induction. Morpholino oligonucleotide-mediated depletion of Id3 results in the absence of neural crest precursors and a resultant loss of neural crest derivatives. This appears to be mediated by cell cycle inhibition followed by cell death of the neural crest progenitor pool, rather than a cell fate switch. Conversely, overexpression of Id3 increases cell proliferation and results in expansion of the neural crest domain. Our data suggest that Id3 functions by a novel mechanism, independent of cell fate determination, to mediate the decision of neural crest precursors to proliferate or die. [Keywords: Xenopus; Id3; neural crest; cell cycle; survival] Received September 1, 2004; revised version accepted January 19, 2005. The neural crest is an embryonic cell population that origi- et al. 2003), c-Myc (Bellmeyer et al. 2003), and Msx1 nates from the lateral edges of the neural plate during (Tribulo et al. 2003) have been identified in Xenopus nervous system formation.
    [Show full text]
  • Lncmyod Promotes Skeletal Myogenesis and Regulates Skeletal Muscle Fiber-Type Composition by Sponging Mir-370-3P
    G C A T T A C G G C A T genes Article LncMyoD Promotes Skeletal Myogenesis and Regulates Skeletal Muscle Fiber-Type Composition by Sponging miR-370-3p Peiwen Zhang 1,2,† , Jingjing Du 1,2,†, Xinyu Guo 1,2, Shuang Wu 1,2, Jin He 1,2 , Xinrong Li 1,2, Linyuan Shen 1,2 , Lei Chen 1,2, Bohong Li 1, Jingjun Zhang 1, Yuhao Xie 1, Lili Niu 1,2, Dongmei Jiang 1,2, Xuewei Li 1,2, Shunhua Zhang 1,2 and Li Zhu 1,2,* 1 College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China; [email protected] (P.Z.); [email protected] (J.D.); [email protected] (X.G.); [email protected] (S.W.); [email protected] (J.H.); [email protected] (X.L.); [email protected] (L.S.); [email protected] (L.C.); [email protected] (B.L.); [email protected] (J.Z.); [email protected] (Y.X.); [email protected] (L.N.); [email protected] (D.J.); [email protected] (X.L.); [email protected] (S.Z.) 2 Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: The development of skeletal muscle is a highly ordered and complex biological process. Increasing evidence has shown that noncoding RNAs, especially long-noncoding RNAs (lncRNAs) and microRNAs, play a vital role in the development of myogenic processes.
    [Show full text]
  • The NANOG Transcription Factor Induces Type 2 Deiodinase Expression and Regulates the Intracellular Activation of Thyroid Hormone in Keratinocyte Carcinomas
    Cancers 2020, 12 S1 of S18 Supplementary Materials: The NANOG Transcription Factor Induces Type 2 Deiodinase Expression and Regulates the Intracellular Activation of Thyroid Hormone in Keratinocyte Carcinomas Annarita Nappi, Emery Di Cicco, Caterina Miro, Annunziata Gaetana Cicatiello, Serena Sagliocchi, Giuseppina Mancino, Raffaele Ambrosio, Cristina Luongo, Daniela Di Girolamo, Maria Angela De Stefano, Tommaso Porcelli, Mariano Stornaiuolo and Monica Dentice Figure S1. Strategy for the mutagenesis of Dio2 promoter. (A) Schematic representation of NANOG Binding Site within the Dio2 promoter region. (B) Schematic diagram for site‐directed mutagenesis of NANOG Binding Site on Dio2 promoter region by Recombinant PCR. (C) Representation of the mutated NANOG Binding Site on Dio2 promoter region. (D) Electropherogram of the NANOG Binding Site mutation within the Dio2 promoter. Cancers 2020, 12 S2 of S18 Figure S2. Strategy for the silencing of NANOG expression. (A) Cloning strategies for the generation of NANOG shRNA expression vectors. (B) Electropherograms of the NANOG shRNA sequences cloned into pcDNA3.1 vector. (C) Validation of effective NANOG down-modulation by two different NANOG shRNA vectors was assessed by Western Blot analysis of NANOG expression in BCC cells. (D) Quantification of NANOG protein levels versus Tubulin levels in the same experiment as in C is represented by histograms. Cancers 2020, 12 S3 of S18 Figure S3. The CD34+ cells are characterized by the expression of typical epithelial stemness genes. The mRNA levels of a panel of indicated stemness markers of epidermis were measured by Real Time PCR in the same experiment indicated in figure 3F and G. Cancers 2020, 12 S4 of S18 Figure S4.
    [Show full text]
  • Genetic Factors in Nonsyndromic Orofacial Clefts
    Published online: 2021-02-12 THIEME Review Article 101 Genetic Factors in Nonsyndromic Orofacial Clefts Mahamad Irfanulla Khan1 Prashanth C.S.2 Narasimha Murthy Srinath3 1 Department of Orthodontics & Dentofacial Orthopedics, The Oxford Address for correspondence Mahamad Irfanulla Khan, BDS, MDS, Dental College, Bangalore, Karnataka, India Department of Orthodontics & Dentofacial Orthopedics, The Oxford 2 Department of Orthodontics & Dentofacial Orthopedics, DAPM R.V. Dental College, Bangalore, Karnataka 560068, India Dental College, Bangalore, Karnataka, India (e-mail: [email protected]). 3 Department of Oral & Maxillofacial Surgery, Krishnadevaraya College of Dental Sciences, Bangalore, Karnataka, India Global Med Genet 2020;7:101–108. Abstract Orofacial clefts (OFCs) are the most common congenital birth defects in humans and immediately recognized at birth. The etiology remains complex and poorly understood and seems to result from multiple genetic and environmental factors along with gene– environment interactions. It can be classified into syndromic (30%) and nonsyndromic (70%) clefts. Nonsyndromic OFCs include clefts without any additional physical or Keywords cognitive deficits. Recently, various genetic approaches, such as genome-wide associ- ► orofacial clefts ation studies (GWAS), candidate gene association studies, and linkage analysis, have ► nonsyndromic identified multiple genes involved in the etiology of OFCs. ► genetics This article provides an insight into the multiple genes involved in the etiology of OFCs. ► gene mutation Identification of specific genetic causes of clefts helps in a better understanding of the ► genome-wide molecular pathogenesis of OFC. In the near future, it helps to provide a more accurate association study diagnosis, genetic counseling, personalized medicine for better clinical care, and ► linkage analysis prevention of OFCs.
    [Show full text]
  • Tumor and Stem Cell Biology Research
    Published OnlineFirst September 17, 2012; DOI: 10.1158/0008-5472.CAN-12-0614 Cancer Tumor and Stem Cell Biology Research OTX2 Represses Myogenic and Neuronal Differentiation in Medulloblastoma Cells Ren-Yuan Bai1, Verena Staedtke1, Hart G. Lidov3, Charles G. Eberhart2, and Gregory J. Riggins1 Abstract The brain development transcription factor OTX2 is overexpressed and/or genomically amplified in most medulloblastomas, but the mechanistic basis for its contributions in this setting are not understood. In this study, we identified OTX2 as a transcriptional repressor and a gatekeeper of myogenic and neuronal differentiation in medulloblastoma cells. OTX2 binds to the MyoD1 core enhancer through its homeobox domain, and the remarkable repressor activity exhibited by the homeobox domain renders OTX2 transcrip- tionally repressive. RNA interference–mediated attenuation of OTX2 expression triggered myogenic and neuronal differentiation in vitro and prolonged the survival in an orthotopic medulloblastoma mouse model. Conversely, inducing myogenic conversion of medulloblastoma cells led to the loss of OTX2 expression. In medullomyoblastoma, a medulloblastoma subtype containing muscle elements, myogenic cells share cytogenetic signatures with the primitive tumor cells and OTX2 expression was lost in the differentiated myogenic cells. Thus, OTX2 functions via its homeobox domain as a suppressor of differentiation, and the loss of OTX2 expression is linked to the myogenesis in medullomyoblastoma. Together, our findings illustrate the origin of muscle cells in medullomyoblastomas and the oncogenic mechanism of OTX2 as a repressor of diverse differentiating potential. Cancer Res; 72(22); 1–14. Ó2012 AACR. Introduction is featured with rhabdomyoblastic elements immunoreactive Medulloblastoma, the most common type of pediatric brain to desmin, myoglobin, and fast myosin (3).
    [Show full text]
  • Identification of Shared and Unique Gene Families Associated with Oral
    International Journal of Oral Science (2017) 9, 104–109 OPEN www.nature.com/ijos ORIGINAL ARTICLE Identification of shared and unique gene families associated with oral clefts Noriko Funato and Masataka Nakamura Oral clefts, the most frequent congenital birth defects in humans, are multifactorial disorders caused by genetic and environmental factors. Epidemiological studies point to different etiologies underlying the oral cleft phenotypes, cleft lip (CL), CL and/or palate (CL/P) and cleft palate (CP). More than 350 genes have syndromic and/or nonsyndromic oral cleft associations in humans. Although genes related to genetic disorders associated with oral cleft phenotypes are known, a gap between detecting these associations and interpretation of their biological importance has remained. Here, using a gene ontology analysis approach, we grouped these candidate genes on the basis of different functional categories to gain insight into the genetic etiology of oral clefts. We identified different genetic profiles and found correlations between the functions of gene products and oral cleft phenotypes. Our results indicate inherent differences in the genetic etiologies that underlie oral cleft phenotypes and support epidemiological evidence that genes associated with CL/P are both developmentally and genetically different from CP only, incomplete CP, and submucous CP. The epidemiological differences among cleft phenotypes may reflect differences in the underlying genetic causes. Understanding the different causative etiologies of oral clefts is
    [Show full text]
  • Genomic Analysis of Estrogen Cascade Reveals Histone Variant H2A.Z Associated with Breast Cancer Progression
    Molecular Systems Biology 4; Article number 188; doi:10.1038/msb.2008.25 Citation: Molecular Systems Biology 4:188 & 2008 EMBO and Nature Publishing Group All rights reserved 1744-4292/08 www.molecularsystemsbiology.com Genomic analysis of estrogen cascade reveals histone variant H2A.Z associated with breast cancer progression Sujun Hua1,2,3,9, Caleb B Kallen4,9, Ruby Dhar1,2, Maria T Baquero5, Christopher E Mason6, Beth A Russell1,2,6, Parantu K Shah1,2, Jiang Liu1,2, Andrey Khramtsov7, Maria S Tretiakova8, Thomas N Krausz8, Olufunmilayo I Olopade7, David L Rimm5 and Kevin P White1,2,* 1 Joint Institute for Genomics and Systems Biology, The University of Chicago and Argonne National Laboratory, Chicago, IL, USA, 2 Department of Human Genetics, The University of Chicago, Chicago, IL, USA, 3 Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA, 4 Department of Gynecology and Obstetrics, Emory University, Atlanta, GA, USA, 5 Department of Pathology, Yale University, New Haven, CT, USA, 6 Department of Genetics, Yale University, New Haven, CT, USA, 7 Center for Clinical Cancer Genetics, University of Chicago Medical Center, Chicago, IL, USA and 8 Department of Pathology, The University of Chicago Hospitals, Chicago, IL, USA 9 These authors contributed equally to this work * Corresponding author. Department of Human Genetics, The University of Chicago, 1639 Pierce Drive, WMB 4211, Chicago, IL 60637, USA. Tel.: þ 1 773 834 8259; Fax: þ 1 773 834 0505; E-mail: [email protected] Received 7.9.07; accepted 13.3.08 We demonstrate an integrated approach to the study of a transcriptional regulatory cascade involved in the progression of breast cancer and we identify a protein associated with disease progression.
    [Show full text]
  • (Rs13041247 and Rs11696257) and Risk of Non-Syndromic Cleft Lip/Palate: Systematic Review and Meta-Analysis
    International Journal of Environmental Research and Public Health Review Polymorphic Variants of V-Maf Musculoaponeurotic Fibrosarcoma Oncogene Homolog B (rs13041247 and rs11696257) and Risk of Non-Syndromic Cleft Lip/Palate: Systematic Review and Meta-Analysis Mohammad Moslem Imani 1, Pia Lopez-Jornet 2 , Eduardo Pons-Fuster López 3 and Masoud Sadeghi 4,5,* 1 Department of Orthodontics, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah 6713954658, Iran 2 Facultad de Medicina y Odontologia Universidad de Murcia, Hospital Morales Meseguer, Clinica Odontologic Adv Marques Velez s/n, 30008 Murcia, Spain 3 Insitituto Murciano de Investigación Biomédica, Murcia, Campus de Ciencias de la Salud, Carretera Buenavista s/n, El Palmar, 30120 Murcia, Spain 4 Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah 6714415185, Iran 5 Students Research Committee, Kermanshah University of Medical Sciences, Kermanshah 6715847141, Iran * Correspondence: [email protected] Received: 27 May 2019; Accepted: 2 August 2019; Published: 5 August 2019 Abstract: Background: Non-syndromic cleft lip/palate (NSCL/P) has an etiology, including both genetic and environmental factors. Herein, we evaluated the association of rs13041247 and rs11696257 v-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) polymorphisms with the risk of NSCL/P in a meta-analysis. Methods: The PubMed/Medline, Scopus, Cochrane Library, Web of Science, and HuGE Navigator databases were systematically searched to retrieve relevant articles published up to January 2019. The Newcastle–Ottawa scale was applied for quality evaluation of retrieved articles. The 95% confidence interval (CI) and crude odds ratio (OR) were calculated for each study using the Review Manager 5.3 software to show the association between MAFB polymorphisms and risk of NSCL/P.
    [Show full text]