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Brain-Region-Specific Contributions of Foxp1 to Autism And

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BRAIN-REGION-SPECIFIC CONTRIBUTIONS OF FOXP1 TO AUTISM AND INTELLECTUAL DISABILITY PHENOTYPES Daniel John Araujo APPROVED BY SUPERVISORY COMMITTEE: Amelia J. Eisch, Ph.D. (Chair) _____________________________ Genevieve Konopka, Ph.D. (Mentor) _____________________________ Craig M. Powell, M.D., Ph.D. _____________________________ Lenora J. Volk, Ph.D. _____________________________ Jiang Wu, Ph.D. _____________________________ DEDICATION I would like to thank my thesis advisor Dr. Genevieve Konopka who has always pushed me to strive for excellence in my work. It’s been an honor to study neuroscience under her supervision and she will serve as an example for the rest of my scientific career. I would like to thank my wife Sarah Teresita Vega for her unwavering love and patience. Sarah has been my best friend for the past nine years and her encouragement has allowed me to face any challenge with grit. I also thank my thesis committee members for all of their suggestions on how to improve my research. I would like to thank Dr. Timothy Raabe and Dr. Nancy Street for their continuous support of both my undergraduate and graduate career. Finally, I dedicate this dissertation to my grandparents George Cuellar Araujo and Margarita Salinas Araujo who raised my two siblings and me. Any success I’ve had in life belongs to them. ii BRAIN-REGION-SPECIFIC CONTRIBUTIONS OF FOXP1 TO AUTISM AND INTELLECTUAL DISABILITY PHENOTYPES By DANIEL JOHN ARAUJO, B.S. DISSERTATION Presented to the Faculty of the Graduate School of Biomedical Sciences at The University of Texas Southwestern Medical Center In Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY The University of Texas Southwestern Medical Center Dallas, Texas August 11, 2017 iii Copyright By Daniel John Araujo, 2017 All Rights Reserved iv BRAIN-REGION-SPECIFIC CONTRIBUTIONS OF FOXP1 TO AUTISM AND INTELLECTUAL DISABILITY PHENOTPES Publication No. ______________________ Daniel John Araujo, B.S. The University of Texas Southwestern Medical Center, 2017 Supervising Professor: Genevieve Konopka, Ph.D. ABSTRACT Mutations and deletions in the transcription factor FOXP1 are causative for severe forms of autism spectrum disorder (ASD) that are often comorbid with intellectual disability (ID). FOXP1 is enriched throughout the brain, with strong expression in the pyramidal neurons of the neocortex, the CA1/CA2 subfields of the hippocampus, and the medium spiny neurons of the striatum. Understanding the role that FOXP1 plays within these brain regions could allow for management of ASD and ID symptoms. This v doctoral dissertation leverages multidisciplinary techniques and Foxp1 mutant mouse models to ascertain the role of Foxp1 in the brain and its contribution to specific ASD- and ID-relevant phenotypes. In the first chapter of this dissertation, I review the literature on the characteristics, demographics, and shared genetic underpinnings of ASD and ID and I review the work linking FOXP1 to these disorders. Afterwards, I describe the regional transcriptome regulated by Foxp1 within the brain and I correlate alterations in the gene expression profile of the striatum with deficits in communication (Chapter 2). Briefly, I utilized RNA-sequencing performed on Foxp1 heterozygous knockout animals to uncover the genes regulated by Foxp1 within the neocortex, hippocampus, and striatum. I also recorded the early postnatal ultrasonic vocalizations (USVs) of these animals and I was able to correlate changes in the properties of striatal medium spiny neurons with deficits in USV production. Next, I move onto using a Foxp1 conditional knockout (Foxp1cKO) mouse model to ascertain the contributions of Foxp1 in the neocortex and the hippocampus to ASD and ID-related behaviors (Chapter 3). In brief, I show that total loss of Foxp1 in the pyramidal neurons of the neocortex and the CA1/2 hippocampal subfields results in social communication deficits as well as hyperactivity and anxiety-like behaviors. I also show that Foxp1cKO mice display gross impairments in hippocampal-based spatial-learning tasks and I correlate these deficits with alterations in the expression of genes involved in hippocampal physiology and synaptic plasticity. In my final chapter (Chapter 4), I consider the implications that these data have on our understanding of the role that Foxp1 plays within the brain and I suggest research strategies to answer the new questions that my findings have vi generated. I also discuss the implications that this research has on our understanding of ASD and ID pathophysiology in general and I recommend future directions for work focused on managing these disorders. vii TABLE OF CONTENTS PRIOR PUBLICATIONS …………………………………………………………….……….. xi LIST OF FIGURES ………………………………………………………………….……….. xii LIST OF TABLES …………………………………………………………………….……... xiv LIST OF DEFINITIONS ……………………………………………………………….……... xv LIST OF ABREVIATIONS …………………………………………………………….……. xvi CHAPTER ONE: Introduction ……………………………………………………….……… 1 Overview ………………………………………………………………………….……. 1 Autism Spectrum Disorder and Intellectual Disability ……….......................... 2 Clinical Features of Autism Spectrum Disorder ……………….………..…... 2 Clinical Features of Intellectual Disability ………………………...……….… 4 Overlapping Demographics Between ASD and ID ……………….………... 6 Genetics of ASD and ID ……………………………….……………..……….. 7 Evidence Supporting a Role for FOXP1 in ASD and ID ……..…..……………. 11 FOXP1 as a Transcription Factor ………………………………..………….. 11 FOXP1 as a High-Confidence ASD- and ID- Risk Gene …....................... 14 Known Functions of FOXP1 Within the Brain ……………………..…………… 17 Neuronal Functions of FoxP1 in vitro and in vivo ……..…………..………. 17 FoxP1 and FoxP2 in the Regulation of Vocal Communication …………... 21 Questions Addressed in This Thesis ……………………………………….…… 23 Figures ……………………………………………………………………….……….. 25 Tables ……………………………………………………………………….………… 28 viii References …………………………………………………………………………... 31 CHAPTER TWO: FOXP1 Orchestration of ASD-Relevant Signaling Pathways in the Striatum ………………………………………………………………………….………….... 39 Abstract …………………………………………………………………….………… 39 Introduction ………………………………………………………………….………. 40 Materials and Methods ……………………………………………………….……. 42 Results ………………………………………………………………………….…….. 56 Discussion ……………………………………………………………………….…... 67 Figures …………………………………………………………………………….….. 72 Tables ……………………………………………………………………………….… 96 References …………………………………………………………………………. 144 CHAPTER THREE: Foxp1 in Forebrain Pyramidal Neurons Controls Gene Expression Required for Spatial Learning and Synaptic Plasticity …………..…... 149 Abstract ………………………………………………………………………….….. 149 Introduction ……………………………………………………………………...… 150 Materials and Methods ………………………………………….………………... 153 Results …………………………………………………………….………………… 168 Discussion ………………………………………………………………….………. 180 Figures ……………………………………………………………………….……… 186 Tables …………………………………………………………………………….…. 202 References …………………………………………………………………………. 231 CHAPTER FOUR: Discussion and Future Directions …………….……………….… 236 ix Overview …………………………………………………………………….……… 236 Materials and Methods …………………………………………………………… 237 Chapter 2 ………………………………………………….………………………… 240 Discussion …………………………………………………………………... 240 Remaining Questions and Future Directions ………………..…………… 241 Chapter 3 ………………………….………………………………………………… 244 Discussion …………………………………………………………………... 244 Remaining Questions and Future Directions ……………………..…….... 245 Final Remarks …………………………………………………………..………..… 252 Figures ………………………………………………………….…………………… 254 Tables ……………………………………………………………………………….. 271 References …………………………………………………………………………. 282 VITAE ………………………………………………………………….…………………….. 284 x PRIOR PUBLICATIONS Research Usui, N., Araujo, D.J., Kulkarni, A., Ellegood, J., Co, M., Ellegood, J., Harper, M., Torimui, K., Lerch, J.P., Konopka, G. Foxp1 regulation of neonatal vocal and motor behaviors via cortical development. Submitted to Genes and Development for peer-review. Araujo, D.J., Toriumi, K., Escamilla, C.O., Kulkarni, A., Anderson, A.G., Harper, M., Usui, N., Ellegood, J., Lerch, J.P., Birnbaum, S.G., Tucker, H.O., Powell, C.M., and Konopka, G. Foxp1 in forebrain pyramidal neurons controls gene expression required for spatial learning and synaptic plasticity. Re-submitted to The Journal of Neuroscience for peer-review. Araujo, D.J.*, Anderson, A.G.*, Berto, S., Runnels, W., Harper, M., Ammanuel, S., Rieger, M.A., Huang, H.C., Rajkovich, K., Loerwald, K.W., Dekker, J.D., Tucker, H.O., Dougherty, J.D., Gibson, J.R., Konopka, G. FoxP1 orchestration of ASD-relevant signaling pathways in the striatum. Genes and Development 29, 2081-2096 (2015). *These authors contributed equally to this work. Macrini, T.E., Coan, H.B., Levine, S.M., Lerma, T., Saks, C.D., Araujo, D.J., Bredbenner, T.L., Coutts, R.D., Nicolella, D.P., Havill, L.M. Reproductive status and sex show strong effects on knee OA in a baboon model. Osteoarthritis and Cartilage 21, 839-848 (2013). Opinion/Resource Araujo, D.J., Nevarez, Andres. The Grassroots Movement to Diversify STEM. SACNAS News 18, No.1, 21-23 (2015). xi LIST OF FIGURES Figure 1.1. Overlapping clinical characteristics of ASD and ID ……..……………..…….. 25 Figure 1.2. Diagram of FOXP1 ……………………………………………………..……….. 26 Figure 1.3. Co-immunopecipitation of Foxp1 with Foxp2 in the mouse striatum ….....… 27 Figure 2.1. Regulation of ASD genes by Foxp1 in the mouse brain …………………..… 72 Figure 2.2. Foxp1 and Foxp2 regulate overlapping targets within the striatum ……..…. 74 + +/− Figure 2.3. D2 MSNs of Foxp1 mice have increased excitability ……………….….…
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    Nova Southeastern University NSUWorks Biology Faculty Articles Department of Biological Sciences 8-22-2019 Avian Binocularity and Adaptation to Nocturnal Environments: Genomic Insights froma Highly Derived Visual Phenotype Rui Borges Universidade do Porto - Portugal Joao Fonseca Universidade do Porto - Portugal Cidalia Gomes Universidade do Porto - Portugal Warren E. Johnson Smithsonian Institution Stephen James O'Brien St. Petersburg State University - Russia; Nova Southeastern University, [email protected] See next page for additional authors Follow this and additional works at: https://nsuworks.nova.edu/cnso_bio_facarticles Part of the Biology Commons NSUWorks Citation Borges, Rui; Joao Fonseca; Cidalia Gomes; Warren E. Johnson; Stephen James O'Brien; Guojie Zhang; M. Thomas P. Gilbert; Erich D. Jarvis; and Agostinho Antunes. 2019. "Avian Binocularity and Adaptation to Nocturnal Environments: Genomic Insights froma Highly Derived Visual Phenotype." Genome Biology and Evolution 11, (8): 2244-2255. doi:10.1093/gbe/evz111. This Article is brought to you for free and open access by the Department of Biological Sciences at NSUWorks. It has been accepted for inclusion in Biology Faculty Articles by an authorized administrator of NSUWorks. For more information, please contact [email protected]. Authors Rui Borges, Joao Fonseca, Cidalia Gomes, Warren E. Johnson, Stephen James O'Brien, Guojie Zhang, M. Thomas P. Gilbert, Erich D. Jarvis, and Agostinho Antunes This article is available at NSUWorks: https://nsuworks.nova.edu/cnso_bio_facarticles/982 GBE Avian Binocularity and Adaptation to Nocturnal Environments: Genomic Insights from a Highly Derived Visual Downloaded from https://academic.oup.com/gbe/article-abstract/11/8/2244/5544263 by Nova Southeastern University/HPD Library user on 16 September 2019 Phenotype Rui Borges1,2,Joao~ Fonseca1,Cidalia Gomes1, Warren E.
  • Viewed and Published Immediately Upon Acceptance Cited in Pubmed and Archived on Pubmed Central Yours — You Keep the Copyright

    Viewed and Published Immediately Upon Acceptance Cited in Pubmed and Archived on Pubmed Central Yours — You Keep the Copyright

    BMC Genomics BioMed Central Research article Open Access Differential gene expression in ADAM10 and mutant ADAM10 transgenic mice Claudia Prinzen1, Dietrich Trümbach2, Wolfgang Wurst2, Kristina Endres1, Rolf Postina1 and Falk Fahrenholz*1 Address: 1Johannes Gutenberg-University, Institute of Biochemistry, Mainz, Johann-Joachim-Becherweg 30, 55128 Mainz, Germany and 2Helmholtz Zentrum München – German Research Center for Environmental Health, Institute for Developmental Genetics, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany Email: Claudia Prinzen - [email protected]; Dietrich Trümbach - [email protected]; Wolfgang Wurst - [email protected]; Kristina Endres - [email protected]; Rolf Postina - [email protected]; Falk Fahrenholz* - [email protected] * Corresponding author Published: 5 February 2009 Received: 19 June 2008 Accepted: 5 February 2009 BMC Genomics 2009, 10:66 doi:10.1186/1471-2164-10-66 This article is available from: http://www.biomedcentral.com/1471-2164/10/66 © 2009 Prinzen et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: In a transgenic mouse model of Alzheimer disease (AD), cleavage of the amyloid precursor protein (APP) by the α-secretase ADAM10 prevented amyloid plaque formation, and alleviated cognitive deficits. Furthermore, ADAM10 overexpression increased the cortical synaptogenesis. These results suggest that upregulation of ADAM10 in the brain has beneficial effects on AD pathology. Results: To assess the influence of ADAM10 on the gene expression profile in the brain, we performed a microarray analysis using RNA isolated from brains of five months old mice overexpressing either the α-secretase ADAM10, or a dominant-negative mutant (dn) of this enzyme.