DOCSLIB.ORG

Development in the Mammalian Auditory System Depends on Transcription Factors

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

International Journal of Molecular Sciences Review Development in the Mammalian Auditory System Depends on Transcription Factors Karen L. Elliott 1, Gabriela Pavlínková 2 , Victor V. Chizhikov 3, Ebenezer N. Yamoah 4 and Bernd Fritzsch 1,* 1 Department of Biology, University of Iowa, Iowa City, IA 52242, USA; [email protected] 2 Institute of Biotechnology of the Czech Academy of Sciences, 25250 Vestec, Czechia; [email protected] 3 Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA; [email protected] 4 Department of Physiology and Cell Biology, School of Medicine, University of Nevada, Reno, NV 89557, USA; [email protected] * Correspondence: [email protected] Abstract: We review the molecular basis of several transcription factors (Eya1, Sox2), including the three related genes coding basic helix–loop–helix (bHLH; see abbreviations) proteins (Neurog1, Neurod1, Atoh1) during the development of spiral ganglia, cochlear nuclei, and cochlear hair cells. Neuronal development requires Neurog1, followed by its downstream target Neurod1, to cross- regulate Atoh1 expression. In contrast, hair cells and cochlear nuclei critically depend on Atoh1 and require Neurod1 expression for interactions with Atoh1. Upregulation of Atoh1 following Neurod1 loss changes some vestibular neurons’ fate into “hair cells”, highlighting the significant interplay between the bHLH genes. Further work showed that replacing Atoh1 by Neurog1 rescues some hair cells from complete absence observed in Atoh1 null mutants, suggesting that bHLH genes can partially replace Citation: Elliott, K.L.; Pavlínková, G.; one another. The inhibition of Atoh1 by Neurod1 is essential for proper neuronal cell fate, and in Chizhikov, V.V.; Yamoah, E.N.; the absence of Neurod1, Atoh1 is upregulated, resulting in the formation of “intraganglionic” HCs. Fritzsch, B. Development in the Additional genes, such as Eya1/Six1, Sox2, Pax2, Gata3, Fgfr2b, Foxg1, and Lmx1a/b, play a role in the Mammalian Auditory System Depends on Transcription Factors. auditory system. Finally, both Lmx1a and Lmx1b genes are essential for the cochlear organ of Corti, Int. J. Mol. Sci. 2021, 22, 4189. spiral ganglion neuron, and cochlear nuclei formation. We integrate the mammalian auditory system https://doi.org/10.3390/ development to provide comprehensive insights beyond the limited perception driven by singular ijms22084189 investigations of cochlear neurons, cochlear hair cells, and cochlear nuclei. A detailed analysis of gene expression is needed to understand better how upstream regulators facilitate gene interactions Academic Editor: Toshio Ohshima and mammalian auditory system development. Received: 13 February 2021 Keywords: transcription factors; neuronal differentiation; bHLH genes; spiral ganglion neurons; Accepted: 16 April 2021 cochlea hair cells; cochlear nuclei Published: 18 April 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- The mammalian auditory system evolved in tetrapods out of the vestibular system [1,2] iations. that diversifies into distinct hair cells with a unique innervation of spiral ganglion neurons (SGNs) which reach the cochlear nuclei for information processing [3,4]. The development of the auditory system depends on sequential activation of various genes. Once early development is completed, age-dependent loss progresses to reduce auditory hair cells Copyright: © 2021 by the authors. that cannot be replaced [5,6]. Loss of hair cells may result in a delayed loss of SGNs with Licensee MDPI, Basel, Switzerland. age [7,8], which will affect the cochlear nuclei [9]. We aim to provide an overview of This article is an open access article transcription factors to allow a framework to develop the auditory system’s earliest steps, distributed under the terms and from neurons to hair cells and cochlear nuclei. conditions of the Creative Commons The mammalian auditory system consists of SGNs, two types of cochlear hair cells Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ (inner and outer hair cells; IHC, OHC), and the cochlear nuclei subdivided into three 4.0/). nuclei: the anteroventral, posteroventral, and dorsal cochlear nucleus. Insights into these Int. J. Mol. Sci. 2021, 22, 4189. https://doi.org/10.3390/ijms22084189 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 21 The mammalian auditory system consists of SGNs, two types of cochlear hair cells Int. J. Mol. Sci. 2021, 22, 4189 2 of 21 (inner and outer hair cells; IHC, OHC), and the cochlear nuclei subdivided into three nu- clei: the anteroventral, posteroventral, and dorsal cochlear nucleus. Insights into these in- terlinked neurosensory components will be detailed beyond the initial morphogenetic interlinkedearly steps neurosensory[9,10]. The proliferation components pattern will be within detailed each beyond auditory the system initial morphogenetic component af- earlyfects the steps temporal [9,10]. The and proliferation spatial differentiation pattern within and interconnects each auditory with system various component neurosensory affects thecells. temporal SGNs are and the spatial first cells differentiation of the auditory and interconnectssystem to exit with the cell various cycle, neurosensory progressing cells.from SGNsbase-to are-apex the from first ~E10.5 cells of–12.5, the auditoryfollowed systemby cochlear to exit HCs, the which cell cycle, exit the progressing cell cycle oppo- from base-to-apexsite direction, from from ~E10.5–12.5, apex-to-base followed between by ~E12.5 cochlear–14.5 HCs, [11, which12]. The exit temporal the cell cyclepattern opposite of pro- direction,liferation fromprogression apex-to-base in the betweencochlea raises ~E12.5–14.5 questions: [11,12 why]. The do temporal developing pattern neurons of prolifer- prolif- ationerate progressionfrom the apex in- theto-base cochlea, and raises the cochlear questions: HCs why proliferate do developing from base neurons-to-apex proliferate (Figure from1)? The the cochlear apex-to-base, nuclei and exit the the cochlear cell cycle HCs between proliferate E10.5 from–14.5 base-to-apex [13], partially (Figure overlapping1)? The cochlearwith spiral nuclei ganglion exit the neurons. cell cycle G betweenranular cells E10.5–14.5 exit the [13 cell], partially cycle between overlapping E12-18, with which spiral is gangliondelayed relativ neurons.e to Granularspiral ganglion cells exitproliferation the cell cycle progression between [14] E12-18,. We want which to is follow delayed the relativeformation to spiralof SGN ganglions, hair cells, proliferation and cochlear progression nuclei and [14 ].relate We wantthem to to follow the three the interlinked formation ofconnections. SGNs, hair cells, and cochlear nuclei and relate them to the three interlinked connections. SpiralSpiral ganglionganglion neurons: neurons: SGNs SGNs depend depend upon uponEya1 Eya1and andSox2, Sox2,followed followed by Neurog1 by Neurog[15]1 and[15] Neurod1and Neurod1[16]. [Neurog116]. Neurog1was shownwas shown to be to regulated be regulated by Neurod1 by Neurod1[17]. [ In17] contrast. In contrast to the to completethe complete loss loss of neurons of neurons in Neurog1 in Neurog1null micenull mice [15], [ a15] few, a SGNsfew SGNs remain remain following following the loss the oflossNeurod1 of Neurod1[16,18 [16,]. A18] degree. A degree of interaction of interaction and crosstalkand crosstalk between betweenNeurog1, Neurog1, Neurod1 Neurod1, and, Atoh1and Atoh1and variousand various additional additional transcription transcription factors factors remain remain incompletely incompletely understood understood and willand bewill discussed be discussed in this in review.this review. Figure 1. A composite set of development of the auditory system is revealed—Base-to-apex pro- Figure 1. A composite set of development of the auditory system is revealed—Base-to-apex progres- gression of α9-AChr expression in differentiating hair cells along the cochlea (A,B). The two differ- α sionent types of 9-AChr of spiral expression ganglion neurons in differentiating connect the hair cochlear cells along hair thecells cochlea with the (A cochlear,B). The nuclei two different (ante- typesroventral of spiral (AVCN ganglion), posteroventral neurons connect (PVCN the), cochlear dorsal (DCN hair cells)), maintaining with the cochlear basal to nuclei apical (anteroventral tonotopic (AVCN),representation posteroventral (C). The PVCN, (PVCN), located dorsal in (DCN)),rhombomere maintaining 4, expresses basal Hoxb1. to apical An tonotopicapex-to-base represen- prolif- tationeration (C (E12.5). The–14.5) PVCN, for located cochlear in hair rhombomere cells is followed 4, expresses by a base Hoxb1.-to-apex An differenti apex-to-baseation proliferation initiated by (E12.5–14.5)Atoh1 (E13.5for–P0). cochlear The organ hair of cells Corti is followed contains bytwo a different base-to-apex types differentiation of hair cells, inner initiated and byouter Atoh1 hair (E13.5–P0).cells (IHC, OHC) The organ arranged of Corti from contains high-frequency two different detection types at of the hair base cells, (thick inner basilar and outermembrane) hair cells to (IHC,low-frequency OHC) arranged detection from at the high-frequency apex (thinner detection basilar membrane). at the base Approximately (thick basilar membrane) 15 type I fibers to low- converge on a single IHC, whereas a single
Recommended publications
  • RBP-J Signaling − Cells Through Notch Novel IRF8-Controlled

    RBP-J Signaling − Cells Through Notch Novel IRF8-Controlled

    Sca-1+Lin−CD117− Mesenchymal Stem/Stromal Cells Induce the Generation of Novel IRF8-Controlled Regulatory Dendritic Cells through Notch −RBP-J Signaling This information is current as of September 25, 2021. Xingxia Liu, Shaoda Ren, Chaozhuo Ge, Kai Cheng, Martin Zenke, Armand Keating and Robert C. H. Zhao J Immunol 2015; 194:4298-4308; Prepublished online 30 March 2015; doi: 10.4049/jimmunol.1402641 Downloaded from http://www.jimmunol.org/content/194/9/4298 Supplementary http://www.jimmunol.org/content/suppl/2015/03/28/jimmunol.140264 http://www.jimmunol.org/ Material 1.DCSupplemental References This article cites 59 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/194/9/4298.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 25, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Sca-1+Lin2CD1172 Mesenchymal Stem/Stromal Cells Induce the Generation of Novel IRF8-Controlled Regulatory Dendritic Cells through Notch–RBP-J Signaling Xingxia Liu,*,1 Shaoda Ren,*,1 Chaozhuo Ge,* Kai Cheng,* Martin Zenke,† Armand Keating,‡,x and Robert C.
  • 1 Evidence for Gliadin Antibodies As Causative Agents in Schizophrenia

    1 Evidence for Gliadin Antibodies As Causative Agents in Schizophrenia

    1 Evidence for gliadin antibodies as causative agents in schizophrenia. C.J.Carter PolygenicPathways, 20 Upper Maze Hill, Saint-Leonard’s on Sea, East Sussex, TN37 0LG [email protected] Tel: 0044 (0)1424 422201 I have no fax Abstract Antibodies to gliadin, a component of gluten, have frequently been reported in schizophrenia patients, and in some cases remission has been noted following the instigation of a gluten free diet. Gliadin is a highly immunogenic protein, and B cell epitopes along its entire immunogenic length are homologous to the products of numerous proteins relevant to schizophrenia (p = 0.012 to 3e-25). These include members of the DISC1 interactome, of glutamate, dopamine and neuregulin signalling networks, and of pathways involved in plasticity, dendritic growth or myelination. Antibodies to gliadin are likely to cross react with these key proteins, as has already been observed with synapsin 1 and calreticulin. Gliadin may thus be a causative agent in schizophrenia, under certain genetic and immunological conditions, producing its effects via antibody mediated knockdown of multiple proteins relevant to the disease process. Because of such homology, an autoimmune response may be sustained by the human antigens that resemble gliadin itself, a scenario supported by many reports of immune activation both in the brain and in lymphocytes in schizophrenia. Gluten free diets and removal of such antibodies may be of therapeutic benefit in certain cases of schizophrenia. 2 Introduction A number of studies from China, Norway, and the USA have reported the presence of gliadin antibodies in schizophrenia 1-5. Gliadin is a component of gluten, intolerance to which is implicated in coeliac disease 6.
  • Detection of Interacting Transcription Factors in Human Tissues Using

    Detection of Interacting Transcription Factors in Human Tissues Using

    Myšičková and Vingron BMC Genomics 2012, 13(Suppl 1):S2 http://www.biomedcentral.com/1471-2164/13/S1/S2 PROCEEDINGS Open Access Detection of interacting transcription factors in human tissues using predicted DNA binding affinity Alena Myšičková*, Martin Vingron From The Tenth Asia Pacific Bioinformatics Conference (APBC 2012) Melbourne, Australia. 17-19 January 2012 Abstract Background: Tissue-specific gene expression is generally regulated by combinatorial interactions among transcription factors (TFs) which bind to the DNA. Despite this known fact, previous discoveries of the mechanism that controls gene expression usually consider only a single TF. Results: We provide a prediction of interacting TFs in 22 human tissues based on their DNA-binding affinity in promoter regions. We analyze all possible pairs of 130 vertebrate TFs from the JASPAR database. First, all human promoter regions are scanned for single TF-DNA binding affinities with TRAP and for each TF a ranked list of all promoters ordered by the binding affinity is created. We then study the similarity of the ranked lists and detect candidates for TF-TF interaction by applying a partial independence test for multiway contingency tables. Our candidates are validated by both known protein-protein interactions (PPIs) and known gene regulation mechanisms in the selected tissue. We find that the known PPIs are significantly enriched in the groups of our predicted TF-TF interactions (2 and 7 times more common than expected by chance). In addition, the predicted interacting TFs for studied tissues (liver, muscle, hematopoietic stem cell) are supported in literature to be active regulators or to be expressed in the corresponding tissue.
  • Core Transcriptional Regulatory Circuitries in Cancer

    Core Transcriptional Regulatory Circuitries in Cancer

    Oncogene (2020) 39:6633–6646 https://doi.org/10.1038/s41388-020-01459-w REVIEW ARTICLE Core transcriptional regulatory circuitries in cancer 1 1,2,3 1 2 1,4,5 Ye Chen ● Liang Xu ● Ruby Yu-Tong Lin ● Markus Müschen ● H. Phillip Koeffler Received: 14 June 2020 / Revised: 30 August 2020 / Accepted: 4 September 2020 / Published online: 17 September 2020 © The Author(s) 2020. This article is published with open access Abstract Transcription factors (TFs) coordinate the on-and-off states of gene expression typically in a combinatorial fashion. Studies from embryonic stem cells and other cell types have revealed that a clique of self-regulated core TFs control cell identity and cell state. These core TFs form interconnected feed-forward transcriptional loops to establish and reinforce the cell-type- specific gene-expression program; the ensemble of core TFs and their regulatory loops constitutes core transcriptional regulatory circuitry (CRC). Here, we summarize recent progress in computational reconstitution and biologic exploration of CRCs across various human malignancies, and consolidate the strategy and methodology for CRC discovery. We also discuss the genetic basis and therapeutic vulnerability of CRC, and highlight new frontiers and future efforts for the study of CRC in cancer. Knowledge of CRC in cancer is fundamental to understanding cancer-specific transcriptional addiction, and should provide important insight to both pathobiology and therapeutics. 1234567890();,: 1234567890();,: Introduction genes. Till now, one critical goal in biology remains to understand the composition and hierarchy of transcriptional Transcriptional regulation is one of the fundamental mole- regulatory network in each specified cell type/lineage.
  • Guide to Sensory Processing.Pdf

    Guide to Sensory Processing.Pdf

    Guide to Sensory Processing Prepared by Allison Travnik, MSOTS Level II Fieldwork Student Project Kavitha N Krishnan MS OTR/L Fieldwork Instructor Sensory Processing In order to understand what is going on around us, we need to organize all of the incoming sensory information (Ayres, 2005). The sensory information involves what we see, smell, taste, hear, feel on our body, where our body is in relation to others, and how well we are balanced. This is a lot of information that our brains need to process in order to engage in productive behavior, learn, and form accurate perceptions. Proprioceptive Where are body is in space Tactile Auditory What we feel The noise on our skin around us Sensory Smell Processing The Sight difference What we see scents around us around us Oral Sensory Processing Vestibular The sensations Jean Ayres developed the sensory Our sense of Disorder + balance that food give integration (SI) theory. SI gives us in our mouth meaning to what our senses are recognizing. When the sensations are not being organized properly may notice some of the same qualities in the brain, Ayres compared it to about yourself.It is important to a traffic jam. The traffic jam of remember that everyone has some sensory information can lead to quirks about their sensory processing learning difficulties and problem whether it be a sensitivity to loud behavior (Ayres, 2005). Children noises or dislike of light touch. with Sensory Processing Disorder However the identification of SPD is (SPD) are struggling with this reserved for individuals whose traffic jam. sensory quirks are outside of the Sensory processing is a typical range and affect their daily dynamic and complex theory.
  • Understanding Sensory Processing: Looking at Children's Behavior Through the Lens of Sensory Processing

    Understanding Sensory Processing: Looking at Children's Behavior Through the Lens of Sensory Processing

    Understanding Sensory Processing: Looking at Children’s Behavior Through the Lens of Sensory Processing Communities of Practice in Autism September 24, 2009 Charlottesville, VA Dianne Koontz Lowman, Ed.D. Early Childhood Coordinator Region 5 T/TAC James Madison University MSC 9002 Harrisonburg, VA 22807 [email protected] ______________________________________________________________________________ Dianne Koontz Lowman/[email protected]/2008 Page 1 Looking at Children’s Behavior Through the Lens of Sensory Processing Do you know a child like this? Travis is constantly moving, pushing, or chewing on things. The collar of his shirt and coat are always wet from chewing. When talking to people, he tends to push up against you. Or do you know another child? Sierra does not like to be hugged or kissed by anyone. She gets upset with other children bump up against her. She doesn’t like socks with a heel or toe seam or any tags on clothes. Why is Travis always chewing? Why doesn’t Sierra liked to be touched? Why do children react differently to things around them? These children have different ways of reacting to the things around them, to sensations. Over the years, different terms (such as sensory integration) have been used to describe how children deal with the information they receive through their senses. Currently, the term being used to describe children who have difficulty dealing with input from their senses is sensory processing disorder. _____________________________________________________________________ Sensory Processing Disorder
  • Jmjd2c Facilitates the Assembly of Essential Enhancer-Protein Complexes at the Onset of Embryonic Stem Cell Differentiation Rute A

    Jmjd2c Facilitates the Assembly of Essential Enhancer-Protein Complexes at the Onset of Embryonic Stem Cell Differentiation Rute A

    © 2017. Published by The Company of Biologists Ltd | Development (2017) 144, 567-579 doi:10.1242/dev.142489 STEM CELLS AND REGENERATION RESEARCH ARTICLE Jmjd2c facilitates the assembly of essential enhancer-protein complexes at the onset of embryonic stem cell differentiation Rute A. Tomaz1,JenniferL.Harman2, Donja Karimlou1, Lauren Weavers1, Lauriane Fritsch3, Tony Bou-Kheir1, Emma Bell1, Ignacio del Valle Torres4, Kathy K. Niakan4,CynthiaFisher5, Onkar Joshi6, Hendrik G. Stunnenberg6, Edward Curry1, Slimane Ait-Si-Ali3, Helle F. Jørgensen2 and Véronique Azuara1,* ABSTRACT implantation, a second extra-embryonic lineage, the primitive Jmjd2 H3K9 demethylases cooperate in promoting mouse embryonic endoderm, emerges at the ICM surface. Concurrently, the ICM stem cell (ESC) identity. However, little is known about their maintains its pluripotency as it matures into the epiblast but importance at the exit of ESC pluripotency. Here, we reveal that ultimately goes on to form the three primary germ layers and germ Jmjd2c facilitates this process by stabilising the assembly of cells upon gastrulation (Boroviak and Nichols, 2014; Rossant, mediator-cohesin complexes at lineage-specific enhancers. 2008). Functionally, we show that Jmjd2c is required in ESCs to initiate Pluripotent mouse embryonic stem cells (ESCs) are derived from appropriate gene expression programs upon somatic multi-lineage ICM cells, and can self-renew and faithfully maintain an differentiation. In the absence of Jmjd2c, differentiation is stalled at an undifferentiated state in vitro in the presence of leukaemia inhibitory early post-implantation epiblast-like stage, while Jmjd2c-knockout factor (LIF) and serum components, while preserving their multi- ESCs remain capable of forming extra-embryonic endoderm lineage differentiation capacity (Evans and Kaufman, 1981; Martin, derivatives.
  • 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

    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
  • Genetic Variability in the Italian Heavy Draught Horse from Pedigree Data and Genomic Information

    Genetic Variability in the Italian Heavy Draught Horse from Pedigree Data and Genomic Information

    Supplementary material for manuscript: Genetic variability in the Italian Heavy Draught Horse from pedigree data and genomic information. Enrico Mancin†, Michela Ablondi†, Roberto Mantovani*, Giuseppe Pigozzi, Alberto Sabbioni and Cristina Sartori ** Correspondence: [email protected] † These two Authors equally contributed to the work Supplementary Figure S1. Mares and foal of Italian Heavy Draught Horse (IHDH; courtesy of Cinzia Stoppa) Supplementary Figure S2. Number of Equivalent Generations (EqGen; above) and pedigree completeness (PC; below) over years in Italian Heavy Draught Horse population. Supplementary Table S1. Descriptive statistics of homozygosity (observed: Ho_obs; expected: Ho_exp; total: Ho_tot) in 267 genotyped individuals of Italian Heavy Draught Horse based on the number of homozygous genotypes. Parameter Mean SD Min Max Ho_obs 35,630.3 500.7 34,291 38,013 Ho_exp 35,707.8 64.0 35,010 35,740 Ho_tot 50,674.5 93.8 49,638 50,714 1 Definitions of the methods for inbreeding are in the text. Supplementary Figure S3. Values of BIC obtained by analyzing values of K from 1 to 10, corresponding on the same amount of clusters defining the proportion of ancestry in the 267 genotyped individuals. Supplementary Table S2. Estimation of genomic effective population size (Ne) traced back to 18 generations ago (Gen. ago). The linkage disequilibrium estimation, adjusted for sampling bias was also included (LD_r2), as well as the relative standard deviation (SD(LD_r2)). Gen. ago Ne LD_r2 SD(LD_r2) 1 100 0.009 0.014 2 108 0.011 0.018 3 118 0.015 0.024 4 126 0.017 0.028 5 134 0.019 0.031 6 143 0.021 0.034 7 156 0.023 0.038 9 173 0.026 0.041 11 189 0.029 0.046 14 213 0.032 0.052 18 241 0.036 0.058 Supplementary Table S3.
  • Hearing Loss Epidemic the Hair Cell

    Hearing Loss Epidemic the Hair Cell

    Hearing loss epidemic One in ten (30 million) Americans has hearing loss FUTURE THERAPIES FOR INNER - Causes include heredity, aging, noise exposure, disease EAR REGENERATION - Number is expected to double by 2030 Hearing loss is the #1 birth defect in America Albert Edge - 1 in 1000 newborns is born profoundly deaf Harvard Medical School - 2-3/1000 will have partial/progressive hearing loss Massachusetts Eye and Ear Infirmary Hearing loss prevalence increases with age - 1 in 3 over 65 years has significant hearing loss - Among seniors, hearing loss is the 3rd most prevalent condition 2 The inner ear The hair cell Auditory Hair Bundle Nerve Middle Ear Sensory hairs vibrate, "tip-links"open ion channels into hair cell Ions flow into hair cell, Inner Ear changing its electrical potential Hair External Ear Cells 3 4 1 The nerve fiber Sensorineural hearing loss: Hair cells and nerve fibers Cochlear Implant can directly stimulate Electric potential causes chemical neurotransmitter release from synapse Sensory Cell Loss NeurotransmitterNeurotransmitter diffuses to nerve fiber and excites electrical activity in the form of action potentials Hair Cell Nerve Fiber Loss 5 6 Regeneration of hair cells in chick inner ear Can stem cell-derived inner ear progenitors replace lost hair cells in vivo (and restore hearing)? Normal Hair Cells Damaged Hair Cells Regenerated Hair Cell Bundles Li et al., TMM (2004) 2 Approaches to regenerating inner ear cells Gene therapy I. Generation of inner ear cells by gene therapy • New hair cells: transfer Atoh1 gene II.
  • Multisensory Integration in the Dorsal Cochlear Nucleus: Unit Responses to Acoustic and Trigeminal Ganglion Stimulation

    Multisensory Integration in the Dorsal Cochlear Nucleus: Unit Responses to Acoustic and Trigeminal Ganglion Stimulation

    European Journal of Neuroscience, Vol. 21, pp. 3334–3348, 2005 ª Federation of European Neuroscience Societies Multisensory integration in the dorsal cochlear nucleus: unit responses to acoustic and trigeminal ganglion stimulation S. E. Shore Kresge Hearing Research Institute and Department of Otolaryngology, University of Michigan, 1301 East Ann Street, Ann Arbor, MI 48109, USA Keywords: auditory, guinea pig, multisensory, neural pathways, somatosensory, trigeminal Abstract A necessary requirement for multisensory integration is the convergence of pathways from different senses. The dorsal cochlear nucleus (DCN) receives auditory input directly via the VIIIth nerve and somatosensory input indirectly from the Vth nerve via granule cells. Multisensory integration may occur in DCN cells that receive both trigeminal and auditory nerve input, such as the fusiform cell. We investigated trigeminal system influences on guinea pig DCN cells by stimulating the trigeminal ganglion while recording spontaneous and sound-driven activity from DCN neurons. A bipolar stimulating electrode was placed into the trigeminal ganglion of anesthetized guinea pigs using stereotaxic co-ordinates. Electrical stimuli were applied as bipolar pulses (100 ls per phase) with amplitudes ranging from 10 to 100 lA. Responses from DCN units were obtained using a 16-channel, four-shank electrode. Current pulses were presented alone or preceding 100- or 200-ms broadband noise (BBN) bursts. Thirty percent of DCN units showed either excitatory, inhibitory or excitatory–inhibitory responses to trigeminal ganglion stimulation. When paired with BBN stimulation, trigeminal stimulation suppressed or facilitated the firing rate in response to BBN in 78% of units, reflecting multisensory integration. Pulses preceding the acoustic stimuli by as much as 95 ms were able to alter responses to BBN.
  • Id4: an Inhibitory Function in the Control

    Id4: an Inhibitory Function in the Control

    Id4: an inhibitory function in the control of hair cell formation? Sara Johanna Margarete Weber Thesis submitted to the University College London (UCL) for the degree of Master of Philosophy The work presented in this thesis was conducted at the UCL Ear Institute between September 23rd 2013 and October 19th 2015. 1st Supervisor: Dr Nicolas Daudet UCL Ear Institute, London, UK 2nd Supervisor: Dr Stephen Price UCL Department of Cell and Developmental Biology, London, UK 3rd Supervisor: Prof Guy Richardson School of Life Sciences, University of Sussex, Brighton, UK I, Sara Weber confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Heidelberg, 08.03.2016 ………………………….. Sara Weber 2 Abstract Mechanosensitive hair cells in the sensory epithelia of the vertebrate inner ear are essential for hearing and the sense of balance. Initially formed during embryological development they are constantly replaced in the adult avian inner ear after hair cell damage and loss, while practically no spontaneous regeneration occurs in mammals. The detailed molecular mechanisms that regulate hair cell formation remain elusive despite the identification of a number of signalling pathways and transcription factors involved in this process. In this study I investigated the role of Inhibitor of differentiation 4 (Id4), a member of the inhibitory class V of bHLH transcription factors, in hair cell formation. I found that Id4 is expressed in both hair cells and supporting cells of the chicken and the mouse inner ear at stages that are crucial for hair cell formation.