FOXP2 and Language Alterations in Psychiatric Pathology
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Cellular and Synaptic Network Defects in Autism
Cellular and synaptic network defects in autism The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Peca, Joao, and Guoping Feng. “Cellular and Synaptic Network Defects in Autism.” Current Opinion in Neurobiology 22, no. 5 (October 2012): 866–872. As Published http://dx.doi.org/10.1016/j.conb.2012.02.015 Publisher Elsevier Version Author's final manuscript Citable link http://hdl.handle.net/1721.1/102179 Terms of Use Creative Commons Attribution-Noncommercial-NoDerivatives Detailed Terms http://creativecommons.org/licenses/by-nc-nd/4.0/ NIH Public Access Author Manuscript Curr Opin Neurobiol. Author manuscript; available in PMC 2013 October 01. Published in final edited form as: Curr Opin Neurobiol. 2012 October ; 22(5): 866–872. doi:10.1016/j.conb.2012.02.015. Cellular and synaptic network defects in autism João Peça1 and Guoping Feng1,2 $watermark-text1McGovern $watermark-text Institute $watermark-text for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA 2Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02142, USA Abstract Many candidate genes are now thought to confer susceptibility to autism spectrum disorder (ASD). Here we review four interrelated complexes, each composed of multiple families of genes that functionally coalesce on common cellular pathways. We illustrate a common thread in the organization of glutamatergic synapses and suggest a link between genes involved in Tuberous Sclerosis Complex, Fragile X syndrome, Angelman syndrome and several synaptic ASD candidate genes. When viewed in this context, progress in deciphering the molecular architecture of cellular protein-protein interactions together with the unraveling of synaptic dysfunction in neural networks may prove pivotal to advancing our understanding of ASDs. -
Lrrtms and Neuroligins Bind Neurexins with a Differential Code to Cooperate in Glutamate Synapse Development
The Journal of Neuroscience, June 2, 2010 • 30(22):7495–7506 • 7495 Cellular/Molecular LRRTMs and Neuroligins Bind Neurexins with a Differential Code to Cooperate in Glutamate Synapse Development Tabrez J. Siddiqui, Raika Pancaroglu, Yunhee Kang, Amanda Rooyakkers, and Ann Marie Craig Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada Leucine-rich repeat transmembrane neuronal proteins (LRRTMs) were recently found to instruct presynaptic and mediate postsynaptic glutamatergic differentiation. In a candidate screen, here we identify neurexin-1 lacking an insert at splice site 4 (ϪS4) as a ligand for LRRTM2. Neurexins bind LRRTM2 with a similar affinity but distinct code from the code for binding neuroligin-1 (the predominant form of neuroligin-1 at glutamate synapses, containing the B splice site insert). Whereas neuroligin-1 binds to neurexins 1, 2, and 3  but not ␣ variants, regardless of insert at splice site 4, LRRTM2 binds to neurexins 1, 2, and 3 ␣ and  variants specifically lacking an insert at splicesite4.WefurthershowthatthisbindingcodeisconservedinLRRTM1,thefamilymemberlinkedtoschizophreniaandhandedness, and that the code is functional in a coculture hemisynapse formation assay. Mutagenesis of LRRTM2 to prevent binding to neurexins abolishes presynaptic inducing activity of LRRTM2. Remarkably, mutagenesis of neurexins shows that the binding face on neurexin-1 (ϪS4) is highly overlapping for the structurally distinct LRRTM2 and neuroligin-1 partners. Finally, we explore here the interplay of neuroligin-1 and LRRTM2 in synapse regulation. In neuron cultures, LRRTM2 is more potent than neuroligin-1 in promoting synaptic differentiation, and, most importantly, these two families of neurexin-binding partners cooperate in an additive or synergistic manner. -
Environmental and Genetic Factors in Autism Spectrum Disorders: Special Emphasis on Data from Arabian Studies
International Journal of Environmental Research and Public Health Review Environmental and Genetic Factors in Autism Spectrum Disorders: Special Emphasis on Data from Arabian Studies Noor B. Almandil 1,† , Deem N. Alkuroud 2,†, Sayed AbdulAzeez 2, Abdulla AlSulaiman 3, Abdelhamid Elaissari 4 and J. Francis Borgio 2,* 1 Department of Clinical Pharmacy Research, Institute for Research and Medical Consultation (IRMC), Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia; [email protected] 2 Department of Genetic Research, Institute for Research and Medical Consultation (IRMC), Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia; [email protected] (D.N.A.); [email protected] (S.A.) 3 Department of Neurology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia; [email protected] or [email protected] 4 Univ Lyon, University Claude Bernard Lyon-1, CNRS, LAGEP-UMR 5007, F-69622 Lyon, France; [email protected] * Correspondence: [email protected] or [email protected]; Tel.: +966-13-333-0864 † These authors contributed equally to this work. Received: 26 January 2019; Accepted: 19 February 2019; Published: 23 February 2019 Abstract: One of the most common neurodevelopmental disorders worldwide is autism spectrum disorder (ASD), which is characterized by language delay, impaired communication interactions, and repetitive patterns of behavior caused by environmental and genetic factors. This review aims to provide a comprehensive survey of recently published literature on ASD and especially novel insights into excitatory synaptic transmission. Even though numerous genes have been discovered that play roles in ASD, a good understanding of the pathophysiologic process of ASD is still lacking. -
Slitrks Control Excitatory and Inhibitory Synapse Formation with LAR
Slitrks control excitatory and inhibitory synapse SEE COMMENTARY formation with LAR receptor protein tyrosine phosphatases Yeong Shin Yima,1, Younghee Kwonb,1, Jungyong Namc, Hong In Yoona, Kangduk Leeb, Dong Goo Kima, Eunjoon Kimc, Chul Hoon Kima,2, and Jaewon Kob,2 aDepartment of Pharmacology, Brain Research Institute, Brain Korea 21 Project for Medical Science, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, Korea; bDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea; and cCenter for Synaptic Brain Dysfunctions, Institute for Basic Science, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea Edited by Thomas C. Südhof, Stanford University School of Medicine, Stanford, CA, and approved December 26, 2012 (received for review June 11, 2012) The balance between excitatory and inhibitory synaptic inputs, share a similar domain organization comprising three Ig domains which is governed by multiple synapse organizers, controls neural and four to eight fibronectin type III repeats. LAR-RPTP family circuit functions and behaviors. Slit- and Trk-like proteins (Slitrks) are members are evolutionarily conserved and are functionally required a family of synapse organizers, whose emerging synaptic roles are for axon guidance and synapse formation (15). Recent studies have incompletely understood. Here, we report that Slitrks are enriched shown that netrin-G ligand-3 (NGL-3), neurotrophin receptor ty- in postsynaptic densities in rat brains. Overexpression of Slitrks rosine kinase C (TrkC), and IL-1 receptor accessory protein-like 1 promoted synapse formation, whereas RNAi-mediated knock- (IL1RAPL1) bind to all three LAR-RPTP family members or dis- down of Slitrks decreased synapse density. -
Deletion of Α-Neurexin II Results in Autism-Related
OPEN Citation: Transl Psychiatry (2014) 4, e484; doi:10.1038/tp.2014.123 www.nature.com/tp ORIGINAL ARTICLE Deletion of α-neurexin II results in autism-related behaviors in mice J Dachtler1, J Glasper2, RN Cohen1, JL Ivorra1, DJ Swiffen1, AJ Jackson1, MK Harte2, RJ Rodgers3 and SJ Clapcote1 Autism is a common and frequently disabling neurodevelopmental disorder with a strong genetic basis. Human genetic studies have discovered mutations disrupting exons of the NRXN2 gene, which encodes the synaptic adhesion protein α-neurexin II (Nrxn2α), in two unrelated individuals with autism, but a causal link between NRXN2 and the disorder remains unclear. To begin to test the hypothesis that Nrxn2α deficiency contributes to the symptoms of autism, we employed Nrxn2α knockout (KO) mice that genetically model Nrxn2α deficiency in vivo. We report that Nrxn2α KO mice displayed deficits in sociability and social memory when exposed to novel conspecifics. In tests of exploratory activity, Nrxn2α KO mice displayed an anxiety-like phenotype in comparison with wild-type littermates, with thigmotaxis in an open field, less time spent in the open arms of an elevated plus maze, more time spent in the enclosure of an emergence test and less time spent exploring novel objects. However, Nrxn2α KO mice did not exhibit any obvious changes in prepulse inhibition or in passive avoidance learning. Real-time PCR analysis of the frontal cortex and hippocampus revealed significant decreases in the mRNA levels of genes encoding proteins involved in both excitatory and inhibitory transmission. Quantification of protein expression revealed that Munc18-1, encoded by Stxbp1, was significantly decreased in the hippocampus of Nrxn2α KO mice, which is suggestive of deficiencies in presynaptic vesicular release. -
Art of Music, As Harmony of the Spheres and Autism Spectrum Disorder
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 6 September 2016 doi:10.20944/preprints201609.0022.v1 Review Art of Music, as Harmony of the Spheres and Autism Spectrum Disorder Bharathi Geetha *, Thangaraj Sugunadevi, Babu Srija, Nagarajan Laleethambika and Vellingiri Balachandar * Human Molecular Genetics and Stem Cell Laboratory, Department of Human Genetics & Molecular Biology, Bharathiar University, Coimbatore, 641046 Tamil Nadu, India; [email protected] (T.S.); [email protected] (B.S.); [email protected] (N.L.) * Correspondence: [email protected] (B.G.); [email protected] or [email protected] (V.B.); Tel.: +91-814-405-2274 (B.G.); +91-422-242-2514 (V.B.); Fax: +91-422-242-2387 (V.B.) Abstract: Music has the innate potential to reach all parts of the brain, stimulates certain brain areas which are not achievable through other modalities. Music Therapy (MT) is being used for more than a century to treat individuals who needs personalized care. MT optimizes motor, speech and language responsibilities of the brain and improves cognitive performance. Pervasive developmentdisorder (PDD) is a multifaceted, neuro developmental disorder and autism spectrum disorder (ASD) comes under PDD, which is defined by deficiencies in three principal spheres: social connection with others, communicative and normal movement skills. The conventional imaging studies illustrate reduced brain area connectivity in people with ASD, involving selected parts of the brain cortex. People with ASD express much interest in musical activities which engages the brain network areas and improves communication and social skills.The main objective of this review is to analyze the potential role of MT in treating the neurological conditions, particularly ASD. -
Neurexin–Neuroligin Signaling in Synapse Development Ann Marie Craig and Yunhee Kang
Neurexin–neuroligin signaling in synapse development Ann Marie Craig and Yunhee Kang Neurexins and neuroligins are emerging as central organizing and knockdown of neuroligins in culture led to the idea molecules for excitatory glutamatergic and inhibitory that these molecules control the balance of GABAergic GABAergic synapses in mammalian brain. They function as cell and glutamatergic inputs [4,5]. We focus our discussion adhesion molecules, bridging the synaptic cleft. Remarkably, here on studies from the past two years that address how each partner can trigger formation of a hemisynapse: alternative splicing in both neurexin and neuroligin tran- neuroligins trigger presynaptic differentiation and neurexins scripts regulates their function. We also discuss initial trigger postsynaptic differentiation. Recent protein interaction results from studies of knockout mice and disease-linked assays and cell culture studies indicate a selectivity of function mutations. conferred by alternative splicing in both partners. An insert at site 4 of b-neurexins selectively promotes GABAergic synaptic Structure of neurexins and neuroligins function, whereas an insert at site B of neuroligin 1 selectively There are three neurexin genes in mammals, each of promotes glutamatergic synaptic function. Initial knockdown which has both an upstream promoter that is used to and knockout studies indicate that neurexins and neuroligins generate the larger a-neurexins and a downstream pro- have an essential role in synaptic transmission, particularly at moter that is used to generate the b-neurexins (Figure 1) GABAergic synapses, but further studies are needed to assess [6]. Alternative splicing at five sites and N- and O-gly- the in vivo functions of these complex protein families. -
A Molecular Classification of Human Mesenchymal Stromal Cells Florian Rohart1, Elizabeth Mason1, Nicholas Matigian1, Rowland
bioRxiv preprint doi: https://doi.org/10.1101/024414; this version posted August 11, 2015. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Rohart'et'al,'The'MSC'Signature' 1' 1' A Molecular Classification of Human Mesenchymal Stromal Cells 2' Florian Rohart1, Elizabeth Mason1, Nicholas Matigian1, Rowland Mosbergen1, 3' Othmar Korn1, Tyrone Chen1, Suzanne Butcher1, Jatin Patel2, Kerry Atkinson2, 4' Kiarash Khosrotehrani2,3, Nicholas M Fisk2,4, Kim-Anh Lê Cao3 and Christine A 5' Wells1,5* 6' 1 Australian Institute for Bioengineering and Nanotechnology, The University of 7' Queensland, Brisbane, QLD Australia 4072 8' 2 The University of Queensland Centre for Clinical Research, Herston, Brisbane, 9' Queensland, Australia, 4029 10' 3 The University of Queensland Diamantina Institute, Translational Research 11' Institute, Woolloongabba, Brisbane QLD Australia, 4102 12' 4 Centre for Advanced Prenatal Care, Royal Brisbane & Women’s Hospital, Herston, 13' Brisbane, Queensland, Australia, 4029 14' 5 Institute for Infection, Immunity and Inflammation, College of Medical, Veterinary & 15' Life Sciences, The University of Glasgow, Scotland, UK G12 8TA 16' *Correspondence to: Christine Wells, [email protected] 17' bioRxiv preprint doi: https://doi.org/10.1101/024414; this version posted August 11, 2015. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. -
A Widespread Peroxiredoxin-Like Domain Present in Tumor Suppression
Pawłowski et al. BMC Genomics 2010, 11:590 http://www.biomedcentral.com/1471-2164/11/590 RESEARCH ARTICLE Open Access A widespread peroxiredoxin-like domain present in tumor suppression- and progression-implicated proteins Krzysztof Pawłowski2,4*, Anna Muszewska1, Anna Lenart2, Teresa Szczepińska2, Adam Godzik3, Marcin Grynberg1* Abstract Background: Peroxide turnover and signalling are involved in many biological phenomena relevant to human diseases. Yet, all the players and mechanisms involved in peroxide perception are not known. Elucidating very remote evolutionary relationships between proteins is an approach that allows the discovery of novel protein functions. Here, we start with three human proteins, SRPX, SRPX2 and CCDC80, involved in tumor suppression and progression, which possess a conserved region of similarity. Structure and function prediction allowed the definition of P-DUDES, a phylogenetically widespread, possibly ancient protein structural domain, common to vertebrates and many bacterial species. Results: We show, using bioinformatics approaches, that the P-DUDES domain, surprisingly, adopts the thioredoxin-like (Thx-like) fold. A tentative, more detailed prediction of function is made, namely, that of a 2-Cys peroxiredoxin. Incidentally, consistent overexpression of all three human P-DUDES genes in two public glioblastoma microarray gene expression datasets was discovered. This finding is discussed in the context of the tumor suppressor role that has been ascribed to P-DUDES proteins in several studies. Majority of non-redundant P- DUDES proteins are found in marine metagenome, and among the bacterial species possessing this domain a trend for a higher proportion of aquatic species is observed. Conclusions: The new protein structural domain, now with a broad enzymatic function predicted, may become a drug target once its detailed molecular mechanism of action is understood in detail. -
Research2007herschkowitzetvolume Al
Open Access Research2007HerschkowitzetVolume al. 8, Issue 5, Article R76 Identification of conserved gene expression features between comment murine mammary carcinoma models and human breast tumors Jason I Herschkowitz¤*†, Karl Simin¤‡, Victor J Weigman§, Igor Mikaelian¶, Jerry Usary*¥, Zhiyuan Hu*¥, Karen E Rasmussen*¥, Laundette P Jones#, Shahin Assefnia#, Subhashini Chandrasekharan¥, Michael G Backlund†, Yuzhi Yin#, Andrey I Khramtsov**, Roy Bastein††, John Quackenbush††, Robert I Glazer#, Powel H Brown‡‡, Jeffrey E Green§§, Levy Kopelovich, reviews Priscilla A Furth#, Juan P Palazzo, Olufunmilayo I Olopade, Philip S Bernard††, Gary A Churchill¶, Terry Van Dyke*¥ and Charles M Perou*¥ Addresses: *Lineberger Comprehensive Cancer Center. †Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. ‡Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA. reports §Department of Biology and Program in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. ¶The Jackson Laboratory, Bar Harbor, ME 04609, USA. ¥Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. #Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA. **Department of Pathology, University of Chicago, Chicago, IL 60637, USA. ††Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. ‡‡Baylor College of Medicine, Houston, TX 77030, USA. §§Transgenic Oncogenesis Group, Laboratory of Cancer Biology and Genetics. Chemoprevention Agent Development Research Group, National Cancer Institute, Bethesda, MD 20892, USA. Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107, USA. Section of Hematology/Oncology, Department of Medicine, Committees on Genetics and Cancer Biology, University of Chicago, Chicago, IL 60637, USA. -
The Untold Stories of the Speech Gene, the FOXP2 Cancer Gene
www.Genes&Cancer.com Genes & Cancer, Vol. 9 (1-2), January 2018 The untold stories of the speech gene, the FOXP2 cancer gene Maria Jesus Herrero1,* and Yorick Gitton2,* 1 Center for Neuroscience Research, Children’s National Medical Center, NW, Washington, DC, USA 2 Sorbonne University, INSERM, CNRS, Vision Institute Research Center, Paris, France * Both authors contributed equally to this work Correspondence to: Yorick Gitton, email: [email protected] Keywords: FOXP2 factor, oncogene, cancer, prognosis, language Received: March 01, 2018 Accepted: April 02, 2018 Published: April 18, 2018 Copyright: Herrero and Gitton et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT FOXP2 encodes a transcription factor involved in speech and language acquisition. Growing evidence now suggests that dysregulated FOXP2 activity may also be instrumental in human oncogenesis, along the lines of other cardinal developmental transcription factors such as DLX5 and DLX6 [1–4]. Several FOXP family members are directly involved during cancer initiation, maintenance and progression in the adult [5–8]. This may comprise either a pro- oncogenic activity or a deficient tumor-suppressor role, depending upon cell types and associated signaling pathways. While FOXP2 is expressed in numerous cell types, its expression has been found to be down-regulated in breast cancer [9], hepatocellular carcinoma [8] and gastric cancer biopsies [10]. Conversely, overexpressed FOXP2 has been reported in multiple myelomas, MGUS (Monoclonal Gammopathy of Undetermined Significance), several subtypes of lymphomas [5,11], as well as in neuroblastomas [12] and ERG fusion-negative prostate cancers [13]. -
Next-Generation DNA Sequencing Identifies Novel Gene Variants And
www.nature.com/scientificreports OPEN Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific Received: 15 November 2016 Accepted: 08 March 2017 language impairment Published: 25 April 2017 Xiaowei Sylvia Chen1, Rose H. Reader2, Alexander Hoischen3, Joris A. Veltman3,4,5, Nuala H. Simpson2, Clyde Francks1,5, Dianne F. Newbury2,6 & Simon E. Fisher1,5 A significant proportion of children have unexplained problems acquiring proficient linguistic skills despite adequate intelligence and opportunity. Developmental language disorders are highly heritable with substantial societal impact. Molecular studies have begun to identify candidate loci, but much of the underlying genetic architecture remains undetermined. We performed whole-exome sequencing of 43 unrelated probands affected by severe specific language impairment, followed by independent validations with Sanger sequencing, and analyses of segregation patterns in parents and siblings, to shed new light on aetiology. By first focusing on a pre-defined set of known candidates from the literature, we identified potentially pathogenic variants in genes already implicated in diverse language-related syndromes, including ERC1, GRIN2A, and SRPX2. Complementary analyses suggested novel putative candidates carrying validated variants which were predicted to have functional effects, such as OXR1, SCN9A and KMT2D. We also searched for potential “multiple-hit” cases; one proband carried a rare AUTS2 variant in combination with a rare inherited haplotype affectingSTARD9 , while another carried a novel nonsynonymous variant in SEMA6D together with a rare stop-gain in SYNPR. On broadening scope to all rare and novel variants throughout the exomes, we identified biological themes that were enriched for such variants, including microtubule transport and cytoskeletal regulation.