DOCSLIB.ORG

Microcephaly-Associated Protein WDR62 Regulates Neurogenesis Through JNK1 in the Developing Neocortex

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Microcephaly-Associated Protein WDR62 Regulates Neurogenesis Through JNK1 in the Developing Neocortex Cell Reports Article Microcephaly-Associated Protein WDR62 Regulates Neurogenesis through JNK1 in the Developing Neocortex Dan Xu,1 Feng Zhang,1 Yaqing Wang,1 Yiming Sun,1 and Zhiheng Xu1,2,* 1State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, West Lincui Road, Chaoyang District, Beijing 100101, China 2Center of Parkinson’s Disease, Beijing Institute for Brain Disorders, Beijing 100101, China *Correspondence: [email protected] http://dx.doi.org/10.1016/j.celrep.2013.12.016 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. SUMMARY somes or mitotic spindle poles (Bilgu¨ var et al., 2010; Guernsey et al., 2010; Hussain et al., 2012; Manzini and Walsh, 2011; Nich- Mutations of WD40-repeat protein 62 (WDR62) have olas et al., 2010; Wollnik, 2010; Yu et al., 2010). Mutations been identified recently to cause human MCPH (auto- in ASPM (MCPH5) and WD40-repeat protein 62 (WDR62; somal-recessive primary microcephaly), a neurode- MCPH2) genes account for more than half of MCPH worldwide velopmental disorder characterized by decreased (Mahmood et al., 2011; Thornton and Woods, 2009). brain size. However, the underlying mechanism is During the initial stages of cortical development, self-renewing unclear. Here, we investigate the function of WDR62 symmetric cell division of progenitors generates sufficient numbers of cells to serve as a pool for ongoing neurogenesis in brain development and the pathological role of WDR62 (Dehay and Kennedy, 2007; Franco and Mu¨ ller, 2013; Huttner mutations. We find that WDR62 knockdown and Kosodo, 2005; Knoblich, 2008; Wang et al., 2011). The pro- leads to premature differentiation of neural pro- liferation and differentiation of NPCs mainly take place in the ven- genitor cells (NPCs). The defect can be rescued by tricular and subventricular zones (VZ and SVZ, respectively). wild-type human WDR62, but not by the five MCPH- Disturbance of the symmetric cell divisions can lead to reduction associated WDR62 mutants. We demonstrate that of the neural progenitor pool, a subsequent decrease in prolifer- WDR62 acts upstream of JNK signaling in the control ation, and decline of neuron production levels. The end result is a of neurogenesis. Depletion of JNK1 and WDR62 in- smaller than usual brain or microcephaly (Dehay and Kennedy, curs very similar defects including abnormal spindle 2007; Huttner and Kosodo, 2005; Manzini and Walsh, 2011; Noc- formation and mitotic division of NPCs as well as pre- tor et al., 2004; Thornton and Woods, 2009; Wollnik, 2010). The mature NPC differentiation during cortical develop- newborn neurons transiently become multipolar with multiple processes within the SVZ and lower intermediate zone (IZ) and ment. Thus, our findings indicate that WDR62 is then change to a bipolar morphology and migrate along radial required for proper neurogenesis via JNK1 and pro- fibers to the cortical plate (CP) where they further mature (Marı´n vide an insight into the molecular mechanisms under- and Rubenstein, 2003; Noctor et al., 2001; Tsai et al., 2005). lying MCPH pathogenesis. Recent studies have identified WDR62 as a causative gene of autosomal recessive microcephaly (Bilgu¨ var et al., 2010; Nicho- INTRODUCTION las et al., 2010; Yu et al., 2010). Similar to our findings for POSH (plenty of SH3 domains) (Kukekov et al., 2006; Xu et al., 2003, Development of the mammalian cortex requires precise timing 2005), WDR62 was originally reported as a scaffold protein for of proliferation/self-renewal of neural progenitor cells (NPCs), the JNK pathway (Cohen-Katsenelson et al., 2011; Wasserman differentiation, neuronal migration, and maturation. Abnormality et al., 2010). WDR62 has 13 WD40 domain repeats in its N-termi- in any of these processes may lead to brain developmental dis- nal half and MKK7/JNK binding domains and six potential JNK orders, such as primary autosomal-recessive microcephaly phosphorylation sites in its C-terminal half. Although WDR62 (MCPH) and lissencephaly (Kaindl et al., 2010; Kang et al., has been proposed to play an important role in spindle formation 2011; Manzini and Walsh, 2011; Marı´n and Rubenstein, 2003; and the proliferation of neuronal progenitor cells (Bilgu¨ var et al., Thornton and Woods, 2009; Tsai et al., 2005). MCPH is a neural 2010; Nicholas et al., 2010; Yu et al., 2010), the exact role of developmental disorder in which patients display significantly WDR62 during cortical development and the underlying mecha- reduced brain size and mental retardation (Mahmood et al., nism by which WDR62 regulates neurogenesis and thereby brain 2011). Interestingly, eight genes (MCPH1–MCPH8) underlying size are unknown. primary microcephaly identified so far are predicted to be asso- In this study, we explore the role of WDR62 in cortical develop- ciated with the function of mitotic apparatus, such as centro- ment. We find that knockdown of WDR62 expression in the rat 104 Cell Reports 6, 104–116, January 16, 2014 ª2014 The Authors A B CD Figure 1. WDR62 Knockdown Results in Altered Cell Distribution and Loss of Radial Glial Fibers (A–C) Coronal sections from rat brains electroporated at E16.5 and inspected at E20.5. Slices were stained with Hoechst for nuclei. WDR62 shRNAs result in reduction of the fraction of cells in the CP and VZ/SVZ but an increase in the IZ. (A and C) Images of cortices electroporated with bicistronic constructs encoding both EGFP and shRNAs, including scrambled (Ctrl) or WDR62-directed small hairpin siRNAs (shW1, shW2, or shW3). Scale bars, 100 mm. (B) Quantification of cell distribution. Data are mean ± SEM. ***p < 0.0001, one-way ANOVA. Ctrl, n = 9; shW1, shW2, and shW3, n = 6. n, brain slice number from different brains. (D) Coronal sections from rat brains electroporated at E16.5 and inspected at E18.5. Slices were stained with GFP antibody in order to detect weak GFP signals. Yellow-boxed areas denote zoomed areas shown in the right two columns. Scale bar, 50 mm. See also Figures S1 and S2. embryonic cortex disturbs the redistribution of newborn neu- line) (Figures S1D–S1G). We used these shRNAs to deplete rons. Wild-type (WT) WDR62, but not the mutants found WDR62 expression in NPCs via in utero electroporation (IUE) in patients with MCPH, can rescue the defects incurred by at embryonic day 16.5 (E16.5) in rat. There were striking differ- WDR62 knockdown. We further demonstrate that WDR62 plays ences in the distribution of transfected cells between WDR62 an essential role in the proliferation and differentiation of NPCs shRNA- and control shRNA-transfected brains inspected through the regulation of JNK1 activity. 4 days (E20.5) or 8 days (postnatal day 2 [P2]) later (Figures 1A and S2A). In the knockdown brains (E20.5), very few cells RESULTS reached the CP, and significantly more cells resided in the IZ compared with controls (Figures 1A and 1B), which apparently WDR62 Knockdown Leads to Defects in NPC correlated well with the knockdown efficacy of shRNAs (Fig- Development that Can Be Rescued by WT WDR62 but ure S1). At P2, most of the WDR62 knockdown cells were Not Mutants Found in Patients with MCPH located in the white matter (WM) of the cerebrum instead (Fig- In order to examine the role of WDR62 in brain development, we ure S2A). More importantly, WDR62 depletion resulted in signif- first assessed the expression of WDR62. In agreement with a icant loss of cells remaining in the proliferative regions of the VZ/ previous report by Nicholas et al. (2010), WDR62 is expressed SVZ 4 days after IUE (Figures 1A–1C). We also did the IUE at E14 in the VZ and SVZ of developing rat forebrain and is located in and inspected the brains at E17.5 and observed similar defects the spindle poles of HEK293 cells in a cell-cycle-dependent as those electroporated at E16.5 and inspected at E20.5 manner (Figures S1A–S1C). We then screened bicistronic con- (Figure S2B). structs encoding both EGFP (or dsRed) and shRNA for WDR62 The decrease of cell number in the VZ/SVZ may be partially knockdown capacity. We found three different shRNAs (shW1, due to cell death because WDR62 knockdown led to a modest shW2, and shW3) capable of knocking down levels of WDR62 increase of cells positive for the activated form of caspase-3 efficiently in different cell types, including cortical neurons and (Figures S2C and S2D). Because neurons are derived from radial mouse neuroblastoma N2a cells (a neural progenitor-like cell glial cells that function as NPCs during brain development to Cell Reports 6, 104–116, January 16, 2014 ª2014 The Authors 105 A Figure 2. WDR62 Knockdown-Incurred Defects Can Be Rescued by WT Human WDR62, but Not Mutants Found in Patients with MCPH (A) Diagram of human WDR62 and sites of different mutants used in (B). (B) WDR62 knockdown-incurred defects can be rescued by human WDR62. Plasmids expressing B either WT or different mutants of human WDR62 were coelectroporated with plasmids expressing control or WDR62 shRNA and analyzed as in Fig- ure 1A. Scale bar, 100 mm. (C) Confirmation of coexpression of WT WDR62 (stained with WDR62 antibody and shown in red) with WDR62 shRNA (green). (D) Quantification of cell distribution in (B). Data are mean ± SEM. ns, p > 0.05, *p < 0.05, **p < 0.01, and ***p < 0.0001, one-way ANOVA. Vector + Ctrl and Vector + shW2 n = 5; all others, n = 3. n, brain slice number from different brains. See also Figure S3. C of the defects incurred by WDR62 knockdown (Figures 2B–2D). In addition, hWDR62 could rescue WDR62 knock- down-incurred defects in a dosage- dependent manner (Figure S3).
Load more

Recommended publications
  • 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]
  • Identification and Characterization of Genes Essential for Human Brain Development
    Identification and Characterization of Genes Essential for Human Brain Development The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Ganesh, Vijay S. 2012. Identification and Characterization of Genes Essential for Human Brain Development. Doctoral dissertation, Harvard University. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:9773743 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Copyright © 2012 by Vijay S. Ganesh All rights reserved. Dissertation Advisor: Dr. Christopher A. Walsh Author: Vijay S. Ganesh Identification and Characterization of Genes Essential for Human Brain Development Abstract The human brain is a network of ninety billion neurons that allows for many of the behavioral adaptations considered unique to our species. One-fifth of these neurons are layered in an epithelial sheet known as the cerebral cortex, which is exquisitely folded into convolutions called gyri. Defects in neuronal number clinically present with microcephaly (Greek for “small head”), and in inherited cases these defects can be linked to mutations that identify genes essential for neural progenitor proliferation. Most microcephaly genes are characterized to play a role in the centrosome, however rarer presentations of microcephaly have identified different mechanisms. Charged multivesicular body protein/Chromatin modifying protein 1A (CHMP1A) is a member of the ESCRT-III endosomal sorting complex, but is also suggested to localize to the nuclear matrix and regulate chromatin.
    [Show full text]
  • Molecular Genetics of Microcephaly Primary Hereditary: an Overview
    brain sciences Review Molecular Genetics of Microcephaly Primary Hereditary: An Overview Nikistratos Siskos † , Electra Stylianopoulou †, Georgios Skavdis and Maria E. Grigoriou * Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece; [email protected] (N.S.); [email protected] (E.S.); [email protected] (G.S.) * Correspondence: [email protected] † Equal contribution. Abstract: MicroCephaly Primary Hereditary (MCPH) is a rare congenital neurodevelopmental disorder characterized by a significant reduction of the occipitofrontal head circumference and mild to moderate mental disability. Patients have small brains, though with overall normal architecture; therefore, studying MCPH can reveal not only the pathological mechanisms leading to this condition, but also the mechanisms operating during normal development. MCPH is genetically heterogeneous, with 27 genes listed so far in the Online Mendelian Inheritance in Man (OMIM) database. In this review, we discuss the role of MCPH proteins and delineate the molecular mechanisms and common pathways in which they participate. Keywords: microcephaly; MCPH; MCPH1–MCPH27; molecular genetics; cell cycle 1. Introduction Citation: Siskos, N.; Stylianopoulou, Microcephaly, from the Greek word µικρoκεϕαλi´α (mikrokephalia), meaning small E.; Skavdis, G.; Grigoriou, M.E. head, is a term used to describe a cranium with reduction of the occipitofrontal head circum- Molecular Genetics of Microcephaly ference equal, or more that teo standard deviations
    [Show full text]
  • Ncomms4885.Pdf
    ARTICLE Received 4 Feb 2014 | Accepted 14 Apr 2014 | Published 30 May 2014 DOI: 10.1038/ncomms4885 Microcephaly disease gene Wdr62 regulates mitotic progression of embryonic neural stem cells and brain size Jian-Fu Chen1,2, Ying Zhang1, Jonathan Wilde1, Kirk C. Hansen3, Fan Lai4 & Lee Niswander1 Human genetic studies have established a link between a class of centrosome proteins and microcephaly. Current studies of microcephaly focus on defective centrosome/spindle orientation. Mutations in WDR62 are associated with microcephaly and other cortical abnormalities in humans. Here we create a mouse model of Wdr62 deficiency and find that the mice exhibit reduced brain size due to decreased neural progenitor cells (NPCs). Wdr62 depleted cells show spindle instability, spindle assembly checkpoint (SAC) activation, mitotic arrest and cell death. Mechanistically, Wdr62 associates and genetically interacts with Aurora A to regulate spindle formation, mitotic progression and brain size. Our results suggest that Wdr62 interacts with Aurora A to control mitotic progression, and loss of these interactions leads to mitotic delay and cell death of NPCs, which could be a potential cause of human microcephaly. 1 Howard Hughes Medical Institute, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children’s Hospital Colorado, Aurora, Colorado 80045, USA. 2 Department of Genetics, Department of Biochemistry & Molecular Biology, University of Georgia, Athens, Georgia 30602, USA. 3 Biochemistry & Molecular Genetics, University of Colorado Denver, Aurora, Colorado 80045, USA. 4 The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA. Correspondence and requests for materials should be addressed to J-F.C. (email: [email protected]) or to L.N.
    [Show full text]
  • (JNK)-Binding Protein WDR62 Is Recruited to Stress Granules And
    Molecular Biology of the Cell Vol. 21, 117–130, January 1, 2010 A Novel c-Jun N-terminal Kinase (JNK)-binding Protein WDR62 Is Recruited to Stress Granules and Mediates a Nonclassical JNK Activation Tanya Wasserman,*† Ksenya Katsenelson,*† Sharon Daniliuc,*† Tal Hasin,* Mordechay Choder,‡ and Ami Aronheim* Departments of *Molecular Genetics and ‡Microbiology, The Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa 31096, Israel Submitted June 22, 2009; Revised October 27, 2009; Accepted October 29, 2009 Monitoring Editor: Jonathan Chernoff The c-Jun N-terminal kinase (JNK) is part of a mitogen-activated protein kinase (MAPK) signaling cascade. Scaffold proteins simultaneously associate with various components of the MAPK signaling pathway and play a role in signal transmission and regulation. Here we describe the identification of a novel scaffold JNK-binding protein, WDR62, with no sequence homology to any of the known scaffold proteins. WDR62 is a ubiquitously expressed heat-sensitive 175-kDa protein that specifically associates with JNK but not with ERK and p38. Association between WDR62 and JNKs occurs in the absence and after either transient or persistent stimuli. WDR62 potentiates JNK kinase activity; however it inhibits AP-1 transcription through recruitment of JNK to a nonnuclear compartment. HEK-293T cells transfected with WDR62 display cytoplasmic granular localization. Overexpression of stress granule (SG) resident proteins results in the recruit- ment of endogenous WDR62 and activated JNK to SG. In addition, cell treatment with arsenite results in recruitment of WDR62 to SG and activated JNK to processing bodies (PB). JNK inhibition results in reduced number and size of SG and reduced size of PB.
    [Show full text]
  • Cenpj Regulates Cilia Disassembly and Neurogenesis in the Developing Mouse Cortex
    This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. A link to any extended data will be provided when the final version is posted online. Research Articles: Development/Plasticity/Repair Cenpj regulates cilia disassembly and neurogenesis in the developing mouse cortex Wenyu Ding1,2, Qian Wu1,2, Le Sun1,2, Na Clara Pan1,2 and Xiaoqun Wang1,2,2 1State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology (Shanghai), Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China 2University of Chinese Academy of Sciences, Beijing 100049, China 3Beijing Institute for Brain Disorders, Beijing 100069, China https://doi.org/10.1523/JNEUROSCI.1849-18.2018 Received: 20 July 2018 Revised: 19 December 2018 Accepted: 24 December 2018 Published: 9 January 2019 Author contributions: W.D., Q.W., and X.W. designed research; W.D., Q.W., L.S., N.C.P., and X.W. performed research; W.D., Q.W., L.S., N.C.P., and X.W. analyzed data; W.D., Q.W., L.S., N.C.P., and X.W. edited the paper; W.D., Q.W., and X.W. wrote the paper; Q.W. and X.W. wrote the first draft of the paper; X.W. contributed unpublished reagents/analytic tools. Conflict of Interest: The authors declare no competing financial interests. We gratefully acknowledge Dr. Bradley Yoder (University of Alabama at Birmingham) kindly shared and transferred the mouse strain to us. We thank Dr. Tian Xue (University of Science and Technology of China) for sharing ARPE19 cell line with us.
    [Show full text]
  • A Novel Single Base Pair Duplication in WDR62 Causes Primary Microcephaly Verena Rupp1, Sobiah Rauf2, Ishrat Naveed2, Windpassinger Christian1 and Asif Mir2*
    Rupp et al. BMC Medical Genetics 2014, 15:107 http://www.biomedcentral.com/1471-2350/15/107 CASE REPORT Open Access A novel single base pair duplication in WDR62 causes primary microcephaly Verena Rupp1, Sobiah Rauf2, Ishrat Naveed2, Windpassinger Christian1 and Asif Mir2* Abstract Background: Primary microcephaly is a disorder of the brain resulting in a reduced head circumference that can come along with intellectual disability but with hardly any other neurological abnormalities. Case presentation: In this study we report on three Pakistani males from a consanguineous family with 2, 4 and 25 years, diagnosed with autosomal recessive primary microcephaly. By genotyping, Sanger sequencing and using bioinformatical approaches the disease causing mutation was identified and evaluated. Conclusion: By using a 250K SNP array, we were able to detect an 11Mb large autozygous region in the MCPH2 locus on chromosome 19q13.12. Sequencing of the associated gene, WDR62, revealed the frameshift causing single base pair duplication, c.2527dupG. This mutation is predicted to affect the structural features of WDR62 which in turn changes the conformation and function of the protein. Aspartic acid (D) at position 843 was found to be conserved among various ortholog species. The present findings will be helpful in genetic diagnosis of patients and future studies of WDR62. Keywords: Autosomal recessive primary microcephaly (MCPH), MCPH2 locus, WDR62, Mutation Background Although sloping foreheads and reduced intelligence are Autosomal recessive primary microcephaly (MCPH) is a very common, they are not listed as a basic criteria for the rare malformation of the head resulting in a circumfer- diagnosis of microcephaly [19,22].
    [Show full text]
  • Modifier Genes in Microcephaly: a Report on WDR62, CEP63, RAD50
    G C A T T A C G G C A T genes Article Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ Ehtisham Ul Haq Makhdoom 1,2,3,†, Syeda Seema Waseem 1,4,†, Maria Iqbal 1,2,4, Uzma Abdullah 5 , Ghulam Hussain 3, Maria Asif 1,4, Birgit Budde 1 , Wolfgang Höhne 1, Sigrid Tinschert 6, Saadia Maryam Saadi 2 , Hammad Yousaf 2, Zafar Ali 7, Ambrin Fatima 8, Emrah Kaygusuz 9 , Ayaz Khan 2 , Muhammad Jameel 2, Sheraz Khan 2 , Muhammad Tariq 2 , Iram Anjum 10 , Janine Altmüller 1, Holger Thiele 1, Stefan Höning 4, Shahid Mahmood Baig 2,8,11, Peter Nürnberg 1,12 and Muhammad Sajid Hussain 1,4,12,* 1 Cologne Center for Genomics (CCG), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; [email protected] (E.U.H.M.); [email protected] (S.S.W.); [email protected] (M.I.); [email protected] (M.A.); [email protected] (B.B.); [email protected] (W.H.); [email protected] (J.A.); [email protected] (H.T.); [email protected] (P.N.) 2 Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE) College, PIEAS, Faisalabad 38000, Pakistan; [email protected] (S.M.S.); [email protected] (H.Y.); [email protected] (A.K.); [email protected] (M.J.); [email protected] (S.K.); [email protected] (M.T.); [email protected] (S.M.B.) 3 Citation: Makhdoom, E.U.H.; Neurochemicalbiology and Genetics Laboratory (NGL), Department of Physiology, Faculty of Life Sciences, Waseem, S.S.; Iqbal, M.; Abdullah, U.; Government College University, Faisalabad 38000, Pakistan; [email protected] 4 Hussain, G.; Asif, M.; Budde, B.; Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany; [email protected] Höhne, W.; Tinschert, S.; Saadi, 5 University Institute of Biochemistry and Biotechnology (UIBB), PMAS-Arid Agriculture University, S.M.; et al.
    [Show full text]
  • UC San Francisco Previously Published Works
    UCSF UC San Francisco Previously Published Works Title Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Permalink https://escholarship.org/uc/item/8tg8p58p Journal Nature, 467(7312) ISSN 0028-0836 Authors Bilgüvar, Kaya Oztürk, Ali Kemal Louvi, Angeliki et al. Publication Date 2010-09-01 DOI 10.1038/nature09327 Peer reviewed eScholarship.org Powered by the California Digital Library University of California HHS Public Access Author manuscript Author Manuscript Author ManuscriptNature. Author ManuscriptAuthor manuscript; Author Manuscript available in PMC 2011 July 04. Published in final edited form as: Nature. 2010 September 9; 467(7312): 207–210. doi:10.1038/nature09327. Whole exome sequencing identifies recessive WDR62 mutations in severe brain malformations Kaya Bilgüvar1,2,3,#, Ali Kemal Öztürk1,2,3,#, Angeliki Louvi1,2, Kenneth Y Kwan2,4, Murim Choi3, Burak Tatli5, Dilek Yalnizoğlu6, Beyhan Tüysüz7, Ahmet Okay Çağlayan8, Sarenur Gökben9, Hande Kaymakçalan10, Tanyeri Barak1,2,3, Mehmet Bakircioğlu1,2,3, Katsuhito Yasuno1,2,3, Winson Ho1,2,3, Stephan Sanders3,11,12, Ying Zhu2,4, Sanem Yilmaz9, Alp Dinçer13, Michele H Johnson1,14,15, Richard A Bronen1,14, Naci Koçer16, Hüseyin Per17, Shrikant Mane18, Mehmet Necmettin Pamir19, Cengiz Yalçinkaya20, Sefer Kumandaş17, Meral Topçu6, Meral Özmen5, Nenad Šestan2,4, Richard P Lifton3,21,*, Matthew W State3,11,12,*, and Murat Günel1,2,3,* 1Department of Neurosurgery, Program on Neurogenetics, Yale University School of Medicine, New Haven CT, 06510, USA
    [Show full text]
  • Opposing Roles for JNK and Aurora a in Regulating the Association Of
    ß 2015. Published by The Company of Biologists Ltd | Journal of Cell Science (2015) 128, 527–540 doi:10.1242/jcs.157537 RESEARCH ARTICLE Opposing roles for JNK and Aurora A in regulating the association of WDR62 with spindle microtubules Nicholas R. Lim1,2,*, Yvonne Y. C. Yeap1,2,*, Teresa T. Zhao1,2, Yan Y. Yip1,2, Shu C. Wong1,2, Dan Xu3, Ching-Seng Ang2, Nicholas A. Williamson2, Zhiheng Xu3, Marie A. Bogoyevitch1,2 and Dominic C. H. Ng1,2,` ABSTRACT commonly mutated MCPH-associated genes encode spindle pole proteins such as ASPM (abnormal spindle-like microcephaly WD40-repeat protein 62 (WDR62) is a spindle pole protein required associated; also known as MCPH5) and WDR62 (WD40- for normal cell division and neuroprogenitor differentiation during repeat protein 62; also known as MCPH2) (Bond et al., 2002; brain development. Microcephaly-associated mutations in WDR62 Wollnik, 2010). Although non-mitotic functions of spindle pole lead to mitotic mislocalization, highlighting a crucial requirement for proteins might contribute to MCPH disease progression, these precise WDR62 spatiotemporal distribution, although the regulatory observations suggest that mitotic spindle architecture and/or mechanisms are unknown. Here, we demonstrate that the WD40- regulation are crucial factors in neural stem cell survival and/or repeat region of WDR62 is required for microtubule association, fate decisions. whereas the disordered C-terminal region regulates cell-cycle- WDR62 is the second most commonly mutated MCPH- dependent compartmentalization. In agreement with a functional associated gene, with .30 nonsense, missense and truncating requirement for the WDR62–JNK1 complex during neurogenesis, frame-shift mutations identified (Nicholas et al., 2010).
    [Show full text]
  • Whole-Exome Sequencing Identifies Recessive WDR62 Mutations in Severe Brain Malformations
    Vol 467 | 9 September 2010 | doi:10.1038/nature09327 LETTERS Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations Kaya Bilgu¨var1,2,3*, Ali Kemal O¨ ztu¨rk1,2,3*, Angeliki Louvi1,2,3, Kenneth Y. Kwan2,4, Murim Choi3, Burak Tatlı5, Dilek Yalnızog˘lu6, Beyhan Tu¨ysu¨z7, Ahmet Okay C¸ag˘layan8, Sarenur Go¨kben9, Hande Kaymakc¸alan10, Tanyeri Barak1,2,3, Mehmet Bakırcıog˘lu1,2,3, Katsuhito Yasuno1,2,3, Winson Ho1,2,3, Stephan Sanders3,11,12, Ying Zhu2,4, Sanem Yılmaz9, Alp Dinc¸er13, Michele H. Johnson1,14,15, Richard A. Bronen1,14, Naci Koc¸er16, Hu¨seyin Per17, Shrikant Mane3,18, Mehmet Necmettin Pamir19, Cengiz Yalc¸ınkaya20, Sefer Kumandas¸17, Meral Topc¸u6, Meral O¨ zmen5, Nenad Sˇestan2,4, Richard P. Lifton3,21, Matthew W. State3,11,12 & Murat Gu¨nel1,2,3 The development of the human cerebral cortex is an orchestrated proliferation, migration or organization. Application of traditional process involving the generation of neural progenitors in the mapping approaches has proved to be particularly challenging for gene periventricular germinal zones, cell proliferation characterized discovery in these syndromes, where kindreds with a single affected by symmetric and asymmetric mitoses, followed by migration of member are most common, linkage studies support high locus hetero- post-mitotic neurons to their final destinations in six highly geneity and recent genetic findings have fundamentally challenged ordered, functionally specialized layers1,2. An understanding of previous diagnostic nosology3,7,8. Based on the expectation that whole- the molecular mechanisms guiding these intricate processes is in exome sequencing using next generation platforms9–11 can markedly its infancy, substantially driven by the discovery of rare mutations improve gene discovery efforts in these situations, we applied this that cause malformations of cortical development3–6.
    [Show full text]
  • Title: Primary Autosomal Recessive Microcephalies and Seckel
    Title: Primary Autosomal Recessive Microcephalies and Seckel Syndrome Spectrum Disorders GeneReview Table 6 Authors: Verloes A, Drunat S, Gressens P, Passemard S Updated: October 2013 Note: The following information is provided by the authors listed above and has not been reviewed by GeneReviews staff. Table 6. Published Pathogenic WDR62 Allelic Variants (Based on NM_001083961.1 and NP_001077430.1 Reference Sequences) DNA Nucleotide Change Protein Amino Acid Change c.193G>A [Nicholas et al 2010, Yu et al 2010] p.Val65Met c.332G>C [Sajid Hussain et al 2013] p.Arg111Thr c.363delT [Yu et al 2010] p.Asp112MetfsTer5 c.535_536insA [Bhat et al 2011] p.Met179fsTer21 c.671G>C [Bilguvar et al 2010] p.Trp224Ser c.900C>A [Bhat et al 2011] p.Cys300Ter c.1043+1G>A [Yu et al 2010] p.Ser348ArgfsTer63 c.1194G>A [Sajid Hussain et al 2013] p.Trp398Ter c.1198G >A [Bacino et al 2012] p.Gln400Lys c.1313G>A [Nicholas et al 2010, Kousar et al 2011, p.Arg438His Sajid Hussain et al 2013] c.1408C>T [Bilguvar et al 2010] p.Gln470Ter c.1143delA [Memon et al 2013] p.His381ProfsTer48 c.1531G>A [Nicholas et al 2010, Kousar et al 2011] p.Asp511Asn c.1576G>T [Bilguvar et al 2010] p.Glu526Ter c.1576G>A [Bilguvar et al 2010] p.Glu526Lys c.1942 C>T [Kousar et al 2011] p.Gln648Ter c.2083delA [Murdock et al 2011] p.Ser696AlafsTer4 c.2867 + 4_c2867 + 7delGGTG [Yu et al 2010] p.Ser956CysfsTer38 c.3232G>A [Nicholas et al 2010] p.Ala1078Thr c.3361delG [Sajid Hussain et al 2013] p.Ala1121GlnfsTer6 DNA Nucleotide Change Protein Amino Acid Change c.3503G>A [Sajid Hussain et al 2013] p.Trp1168 c.3839_3855delGCCAAGAGCCTGCCCTG YU p.Gly1280AfsTer21 [Bilguvar et al 2010] c.3936dupC/c.3936_3937insC [Yu et al 2010, p.Val1314ArgfsTer18/p.Val1313GlyfsTer17 Kousar et al 2011] c.4205delTGCC [Bilguvar et al 2010, Nicholas et al p.Val1402GlyfsTer12 2010] c.4241dupT [Bilguvar et al 2010] p.Leu1414LeufsTer41 See Quick Reference for an explanation of nomenclature.
    [Show full text]