Predoc Program

The Jackson Laboratory PreDoc Program

Opportunities for Predoctoral Research Aging, Bioinformatics, Computational Biology, Cardiovascular Biology, Development, Genomics, Hematology, Immunology/ Inflammation, Metabolism, Neurobiology, Research Tools, Stem Cells

Welcome! The Jackson Laboratory (JAX), an international leader in mammalian genetics research, offers opportunities for Ph.D. research and training in cooperation with degree-granting academic programs. JAX researchers use the outstanding genetic and bioinformatics resources here to investigate normal biology and disease. Students take advantage of the research environment at JAX to conduct dissertation research, for lab rotations, and for short-term collaborative projects. In the following pages are scientific descriptions from Jackson Laboratory faculty who could sponsor predoctoral research.

For more information about the predoctoral program, contact the office of Training and Education ([email protected]), or Mary Ann Handel, Ph.D., Scientific Director of the Predoctoral Program ([email protected]).

600 Main Street Bar Harbor, Maine 04609 USA 207-288-6000 www.jax.org

Judith A. Blake, Ph.D. Associate Professor My research focuses on functional and comparative genome informatics. I work on the development of systems to integrate and analyse genetic, genomic and phenotypic information. I am one of the principal investigators of the Gene Ontology (GO) Consortium, an international effort to provide controlled structured vocabularies for molecular biology that serve as terminologies, classifications and ontologies to further data integration, analysis and reasoning. My interest in bio-ontologies stems as well from the work I do as a principal investigator with the Mouse Genome Informatics (MGI) project at The Jackson Laboratory. The MGI system is a model organism community database resource that provides integrated information about the genetics, genomics and phenotypes of the laboratory mouse. My current research projects combine bio-ontologies and database knowledge systems to analyse disease processes with the objective of discovering new molecular elements and pathways that contribute to particular pathologies such as respiratory diseases.

Bult CJ, Eppig JT, Blake JA, Kadin JA, Richardson JE; the Mouse Genome Database Group. The Mouse Genome Database: Genotypes, Phenotypes, and Models of Human Disease. Nucleic Acids Res. 2013 Jan 1;41(D1):D885-D891. Drabkin HJ, Blake JA; Mouse Genome Informatics Database. Manual Gene Ontology annotation workflow at the Mouse Genome Informatics Database. Database (Oxford). 2012 Oct 29;2012:bas045. Bello SM, Richardson JE, Davis AP, Wiegers TC, Mattingly CJ, Dolan ME, Smith CL, Blake JA, Eppig JT. Disease model curation improvements at Mouse Genome Informatics. Database (Oxford). 2012 Mar 20;2012:bar063. Meehan TF, Carr CJ, Jay JJ, Bult CJ, Chesler EJ, Blake JA. Autism candidate genes via mouse phenomics. J Biomed Inform. 2011 Dec;44 Suppl 1:S5-11. Eppig JT, Blake JA, Bult CJ, Kadin JA, Richardson JE; Mouse Genome Database Group. The Mouse Genome Database (MGD): comprehensive resource for genetics and genomics of the laboratory mouse. Nucleic Acids Res. 2012 Jan;40(Database issue):D881-6. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology 1 www.jax.org/research

Ewelina Bolcun-Filas, Ph.D. Assistant Professor Germ cells are the only cell type that must endure extensive DNA damage in the form of programmed meiotic Double Strand Breaks (DSBs) during their normal development. Paradoxically, the absence of DSBs during meiosis as well as persisting unrepaired breaks are detrimental and typically result in meiotic arrest and infertility. Our research aims to understand the molecular mechanisms controlling the development of healthy gametes and how misregulation of these mechanisms can lead to reproductive disorders. In particular, we are interested in meiotic “quality checkpoints” operating in germ cells, which ensure that the correct and intact genetic information is transmitted to the next generation. The same checkpoint that monitors DSB repair during meiosis is responsible for high sensitivity of oocytes to cancer treatment. Chemo and radiation therapies can cause oocyte death and lead to premature ovarian failure and infertility. Disabling the key checkpoint kinase CHK2 preserved fertility in mice exposed to ionizing radiation, thus opening a new avenue for oncofertility research. Our goal is to further dissect the DNA damage response pathway in oocytes in hope to identify additional targets for fertility preservation therapies in cancer patients.

Singh P, Schimenti JC, Bolcun-Filas E. A Mouse Geneticist’s Practical Guide to CRISPR Applications. Genetics. 2015 Jan:199(1) Bolcun-Filas, E., Rinaldi, V.D., White, M.E., Schimenti, J.C. Reversal of female infertility by Chk2 ablation reveals the oocyte DNA damage checkpoint pathway. Science. 2014 Jan 31; 343 (6170) Li XZ, Roy CK, Dong X, Bolcun-Filas E, Wang J, Han BW, Xu J, Moore MJ, Schimenti JC, Weng Z, Zamore PD. An ancient transcription factor initiates the burst of piRNA production during early meiosis in mouse testes. Mol Cell. 2013 Apr 11;50(1) Bolcun-Filas E, Schimenti JC. Genetics of meiosis and recombination in mice. Int Rev Cell Mol Biol. 2012 Li XC, Bolcun-Filas E, Schimenti JC. Genetic evidence that synaptonemal complex axial elements govern recombination pathway choice in mice. Genetics. 2011 Sep;189(1) Bolcun-Filas E, Bannister LA, Barash A, Schimenti KJ, Hartford SA, Eppig JJ, Handel MA, Shen L, Schimenti JC. A-MYB (MYBL1) transcription factor is a master regulator of male meiosis. Development. 2011 Aug;138(15) Wojtasz L, Daniel K, Roig I, Bolcun-Filas E, Xu H, Boonsanay V, Eckmann CR, Cooke HJ, Jasin M, Keeney S, McKay MJ, Toth A. Mouse HORMAD1 and HORMAD2, two conserved meiotic chromosomal proteins, are depleted from synapsed chromosome axes with the help of TRIP13 AAA-ATPase. PLoS Genet. 2009 Oct;5(10) Bolcun-Filas E, Hall E, Speed R, Taggart M, Grey C, de Massy B, Benavente R, Cooke HJ. Mutation of the mouse Syce1 gene disrupts synapsis and suggests a link between synaptonemal complex structural components and DNA repair. PLoS Genet. 2009 Apr;5(4). Hamer G, Wang H, Bolcun-Filas E, Cooke HJ, Benavente R, Hoog C. Progression of meiotic recombination requires structural maturation of the central element of the synaptonemal complex. J Cell Sci. 2008 Aug 1;121. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology www.jax.org/research 2

Robert Braun, Ph.D. Professor Geneticists measure time in generations and celebrate immortality with reproductive success. My lab is driven by a passion to understand the cell biological basis of gamete (sperm and egg) development. We study how germline stem cells balance self-renewal with differentiation. Stem cell self- renewal at the expense of differentiation can cause germ cell tumors while differentiation at the expense of self-renewal can cause sterility. Our long-term goal is to understand the mechanisms that regulate germline stem cell fate. Other research interests include understanding the molecular function of the hormone testosterone in spermatogenesis. Our work has revealed that specialized tight junctions between Sertoli cells, which are integral to the blood/testis barrier, are regulated by testosterone. We are studying how germ cells pass through these tight junctions without compromising barrier function. We are also investigating molecular mechanisms of translational regulation—a major form of gene regulation in both male and female germ cells—during spermatogenesis. We use both forward and reverse genetics to identify the genes involved. Phenotypic analysis includes microscopy, biochemistry and cell physiology.

Greenlee AR, Shiao MS, Snyder E, Buaas FW, Gu T, Stearns TM, Sharma M, Murchison EP, Puente GC, Braun RE. 2012. Deregulated sex chromosome gene expression with male germ cell-specific loss of Dicer1.PLoS One 7: e46359. Smith BE, Braun RE. Germ cell migration across Sertoli cell tight junctions. Science. 2012 Nov 9;338(6108):798-802. Gu T, Buaas FW, Simons AK, Ackert-Bicknell CL, Braun RE, Hibbs MA. 2011. Canonical A-to-I and C-to-U RNA editing is enriched at 3’ UTRs and microRNA target sites in multiple mouse tissues. PLoS One 7: e33720. Navarro VM, Gottsch ML, Wu M, Garcia-Galiano D, Hobbs SJ, Bosch MA, Pinilla L, Clifton DK, Dearth A, Ronnekleiv OK, Braun RE, Palmiter RD, Tena- Sempere M, Alreja M, Steiner RA. 2011. Regulation of NKB pathways and their roles in the control of Kiss1 neurons in the arcuate nucleus of the male mouse. Endocrinology 152: 4265-4275. PMCID: Meng J, Greenlee AR, Taub CJ, Braun RE. 2011. Sertoli cell-specific deletion of the androgen receptor compromises testicular immune privilege in mice. Biol Reprod 85: 254-260. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology 3 www.jax.org/research

Carol J. Bult, Ph.D. Professor Our research program focuses on two major areas: bioinformatics and developmental genomics. In the area of bioinformatics we focus on building information systems that can facilitate the use of the laboratory mouse as a model system for understanding normative biology and disease processes in humans. We are members of the Mouse Genome Informatics (MGI) consortium and work collaboratively with other investigators at The Jackson Laboratory to build and maintain databases that contain the most comprehensive collection of integrated functional genetic and genomic data for the laboratory mouse available in the public domain. In addition to the MGI information system, we also maintain the Mouse Phenome Database, which contains baseline phenotype measurement for hundreds of traits across scores of inbred lines of mice. Recent projects include the release of a comprehensive gene catalog for the reference mouse genome assembly and the release of MouseCyc, a database of curated biochemical pathways in the laboratory mouse. In the area of developmental genomics, we are working in collaboration with Dr. Isaac Kohane (Children’s Hospital Boston) to use an understanding of the molecular genetics of normal lung development in mouse as a framework for identifying key genes and pathways in lung diseases such as cancer and pulmonary fibrosis. Recent projects include generating an integrated data set of mRNA and microRNA profiles over several key developmental time points in murine lung development.

Bult CJ. 2012. Bioinformatics resources for behavior studies in the laboratory mouse. Rev Neurobiol. 104:71-90. Bult CJ, Eppig JT, Blake JA, Kadin JA, Richardson JE; the Mouse Genome Database Group. The Mouse Genome Database: Genotypes, Phenotypes, and Models of Human Disease. Nucleic Acids Res. 2013 Jan 1;41(D1):D885-D891. Guan Y, Gorenshteyn D, Burmeister M, Wong AK, Schimenti JC, Handel MA, Bult CJ, Hibbs MA, Troyanskaya OG. 2012. Tissue-specific functional networks for prioritizing phenotype and disease genes. PLoS Comput Biol. 8(9):e1002694

Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology www.jax.org/research 4

Robert W. Burgess, Ph.D. Professor The Burgess lab seeks to understand the molecular mechanisms of synapse formation and maintenance at two sites in the nervous system, the peripheral neuromuscular junction and the retina using genetic and neurophysiological approaches in mice. In these studies, we are addressing basic molecular mechanisms, but these basic mechanisms also have relevance to a variety of human diseases including axonal neuropathies and other neuromuscular disorders in the peripheral nervous system and neurodevelopmental conditions such as intellectual disability and Down Syndrome. Our continued research on these genes, and our continuing effort to identify new genes involved in these processes, will increase our understanding of the molecules required to form and maintain synaptic connectivity in the nervous system.

Garrett, A. M., Tadenev, A. L. D., and Burgess R. W. 2012. Dscams: Restoring Balance to Developmental Forces, Frontiers in Mol. Neurosci., 5:86. Motley, W. W., Seburn, K. L., Miers, K. E., Jun, C., Antonellis, A., Green, E.D., Talbot, K., Fischbeck, K. H., and Burgess R. W. 2011. Charcot-Marie-Tooth- linked mutant GARS is toxic to peripheral neurons independent of wild type GARS levels. PLoS Genetics. 7(12), e1002399. Fuerst PG, Bruce F, Tian M, Wei W, Elstrott J, Feller MB, Erskine L, Singer JH, Burgess RW. 2009. DSCAM and DSCAML1 Function in Self-Avoidance in Multiple Cell Types in the Developing Mouse Retina. Neuron. Nov 25; 64(4):484-97. Fuerst PG, Burgess RW. 2009. Adhesion Molecules in establishing retinal circuitry. Curr Opin Neurobiol. 2009 Aug;19(4) 389-394. Fuerst, P. G., Koizumi, A., Masland, R. H., and Burgess, R. W. (2008). Neurite Arborization and Mosaic Spacing in the Mouse Retina Require DSCAM. Nature, Jan. 24, 451(7177) 470-474. Seburn, K. L., Nangle, L. A., Cox, G. A., Schimmel, P., and Burgess, R. W. (2006) An Active Dominant Mutation of Glycyl-tRNA Synthetase Causes Neuropathy in a Charcot-Marie-Tooth 2D Mouse Model. Neuron, Sept. 21, 51(6) 715-726. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology 5 www.jax.org/research

Greg Carter, Ph.D. Assistant Professor A personalized and predictive approach to health and disease will depend on understanding how genes and environmental factors combine to generate complex cellular behaviors. The Carter lab is developing novel computational methods to map complex genetic architecture and infer models that predict the outcomes of genetic and environmental variation. Our work involves deriving network models of interacting genes, integrating disparate phenotypic and molecular data types, critically evaluating models with experimental tests, and understanding how biological information is encoded in genetic networks and genomic data.

Carter GW, Hays M, Sherman A, Galitski T. 2012. Use of pleiotropy to model genetic interactions in a population. PLos Genet 8(10):e1003010. Carter GW, Hays M, Li S, and Galitski T. 2012. Predicting the effects of copy- number variation in double and triple mutant combinations. Symp Biocomput 2012:19-30. Carter GW, Dudley AM. 2009. Systems genetics of complex traits. In: Encyclopedia of Complexity and Systems Science, Robert (Ed), Springer, New York. Carter GW, Galas DJ, and Galitski, T. 2009. Maximal Extraction of Biological Information from Genetic Interaction Data. PLos Comput Biol 5(4):e1000347. Carter GW, Prinz S, Neou C, Shelby JP, Marzolf B, Thorsson V, and Galitski T. 2007. Prediction of phenotype and genomic expression for combinations of mutations. Mol Syst Biol 3:96. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology www.jax.org/research 6

Elissa Chesler, Ph.D. Associate Professor Using bioinformatics and genetics quantitative approaches we enhance the study of behavioral traits in mice through analysis of their underlying genetics and genomics. By integrating findings in mice with data on human behavioral disorders, it is possible to achieve greater validity in relating genetics, environment, and life history to behavior disorders.

Baker EJ, Jay JJ, Bubier JA, Langston MA, Chesler EJ. 2012. GeneWeaver: a web-based system for integrative functional genomics. Nucleic Acids Res 40(Database ):D1067-1076. Bubier JJ, Chesler EJ. 2012. Accelerating discovery for complex neurological and behavioral disorders through systems genetics and integrative genomics in the laboratory mouse. Neurotherapeutics 9(2):338-348. Chesler EJ, Logan RW. 2012. Opportunities for bioinformatics in the classification of behavior and psychiatric disorders.Int Rev Neurobiol (104)183- 211. Dickson PE, Rogers TD, Lester DB, Miller MM, Matta SG, Chesler EJ, Goldowitz D, Blaha CD, Mittleman G. 2011. Genotype-dependent effects of adolescent nicotine exposure on dopamine functional dynamics in the nucleus accumbens shell in male and female mice: a potential mechanism underlying the gateway effect of nicotine.Psychopharmacology 215(4):631-642. Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ. 2010. High-throughput behavioral phenotyping in the expanded panel of BXD recombinant inbred strains. Genes Brain Behav 9(2):129-159. Philip VM, Sokoloff G, Ackert-Bicknell CL, Striz M, Branstetter L, Beckmann MA, Spence JS, Jackson BL, Galloway LD, Barker P, Wymore AM, Hunsicker PR, Durtschi DC, Shaw GS, Shinpock S, Manly KF, Miller DR, Donohue KD, Culiat CT, Churchill GA, Lariviere WR, Palmer AA, O’Hara BF, Voy BH, Chesler EJ. 2011. Genetic analysis in the Collaborative Cross breeding population. Genome Res 21(8):1223-1238. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology 7 www.jax.org/research

Gary A. Churchill, Ph.D. Professor Our lab is actively applying a systems approach to study the genetics of health and disease, incorporating new statistical methods for the investigation of complex disease-related traits in the mouse. We are developing new methods and software that will improve the power of quantitative trait loci mapping and microarray analysis, as well as graphical models which aim to intuitively and precisely characterize the genetic architecture of disease.

Aljakna A, Choi S, Savage H, Hageman Blair R, Gu T, Svenson KL, Churchill GA, Hibbs M, Korstanje R. 2012. Pla2g12b and Hpn are genes identified by mouse ENU mutagenesis that affect HDL cholesterol.PLoS One 7(8):e43139. Blair RH, Kliebenstein DJ, Churchill GA. 2012. What can causal networks tell us about metabolic pathways? What can causal networks tell us about metabolic pathways? PLoS Comput Biol 8(4):e1002458. Churchill GA, Gatti DM, Munger SC, Svenson KL. 2012. The diversity outbred mouse population. Mamm Genome 23(9-10):713-718. PMC3524832 Collaborative Cross Consortium. 2012. The Genome Architecture of the Collaborative Cross Mouse Genetic Reference Population. Genetics 190(2):389- 401. Didion JP, Yang H, Sheppard K, Fu CP, McMillan L, Pardo-Manuel de Villena F, Churchill GA. 2012. Discovery of novel variants in genotyping arrays improves genotype retention and reduces ascertainment bias. BMC Genomics 13(1):34. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology www.jax.org/research 8

Gregory A. Cox, Ph.D. Associate Professor Our lab uses mouse models to identify the molecular pathways underlying degenerative motor neuron diseases in humans, such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease). We cloned the gene for neuromuscular degeneration to create a mouse model for a lethal infantile form of SMA known as spinal muscular atrophy with respiratory distress. Studying the mouse model led to the identification of a modifier gene that decreases disease severity in the mice. In addition, we are working with a transgenic mouse strain (SOD1) to study genetic background effects on progression of an ALS-like disease in the mouse model. We are also studying mouse models for degenerative muscle diseases similar to muscular dystrophy in humans. We cloned a genetic defect and have localized the mutation to the muscle-specific titin gene, the largest known coding gene in the mammalian genome. The mouse strain is a novel model of progressive muscular dystrophy and may also be a model for human tibial muscular dystrophy and limb-girdle muscular dystrophy type 2J. We also identified the mutation for a new form of rostrocaudal muscular dystrophy that affects skeletal muscle tissues in a unusual front-to-back progression.

Stroklin M, Seburn KL, Cox GA, Martens KA, Reiser G. 2012. Severe disturbance in the Ca2+ signaling in astrocytes from mouse models of human infantile neuroaxonal dystrophy with mutated PIa2g6. Hum Mol Genet. 21:2807-2814. Su YQ, Sugiura K, Sun F, Pendola JK, Cox GA, Handel MA, Schimenti JC, Eppig JJ. 2012. MARF1 regulates essential oogenic processes in mice. Science. 335:1496-1499. Choi MC, Cohen TJ, Barrientos T, Wang B, Li M, Simmons BJ, Yang JS, Cox GA, Zhao Y, Yao TP. 2012. A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program. Mol Cell. 47:122-132. Hosur V, Kavirayani R, Riefler J, Carney LM, Lyons B, Gott G, Cox GA, Shultz LD. 2012. Dystrophin and dysferlin double mutant mice: a novel model for rhabdomyosarcoma. Cancer Genet. 205:232-241. Hoffman EP, Gordish-Dressman H, McLane VD, Devaney JM, Thompson PD, Visich P, Gordon PM, Pescatello LS, Zoeller RF, Moyna NM, Angelopoulos TJ, Pegoraro E, Cox GA, Clarkson PM. Alterations in Osteopontin Modify Muscle Size in Females in Both Humans and Mice. Med Sci Sports Exerc. 2012 Dec 27. [Epub ahead of print] Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology 9 www.jax.org/research

Chengkai Dai, M.D., Ph.D. Assistant Professor Our laboratory focuses on understanding the emerging roles of the heat-shock or stress response in human cancers and longevity. The stress response is an evolutionarily highly conserved adaptive mechanism that enhances cell survival in the face of a large variety of stressful insults from without and from within. In mammals, the master transcriptional regulator of this systemic cellular response is heat shock factor 1, HSF1, a pleiotropic molecule that coordinates a network of cellular pathways to fight stresses. One of the major functions of this stress response is to maintain proteome homeostasis under stressful conditions.

Dai C, Dai S, Cao J. 2012. Proteotoxic stress of cancer: implication of the heat- shock response in oncogenesis. J Cell Physiol 227(8):2982-2987. (Review) Dai C, Santagata S, Tang Z, Shi J, Cao J, Kwon H, Bronson RT, Whitesell L, Lindquist S. 2012. Loss of tumor suppressor NF1 activates HSF1 to promote carcinogenesis. J Clin Invest 122(10):3742-3754. Gan N, Wu YC, Brunet M, Garrido C, Chung FL, Dai C, Mi L. 2010. Sulforaphane activates heat shock response and enhances proteasome activity through up-regulation of Hsp27. J Biol Chem 285(46):35528-35536. Dai C, Whitesell L, Rogers A, Lindquist S. 2007. Heat shock factor 1 (HSF1) is a powerful multifaceted modifier of carcinogenesis.Cell 130(6):1005-1018. Dai C, Whitesell L. 2005. Hsp90: a rising star on the horizon of anticancer targets. Future Oncol 1:529-540, review. Dai C, Lyustikman Y, Shih A, Hu X, Fuller GN, Rosenblum M, Holland EC. 2005. The characteristics of astrocytomas and oligodendrogliomas are caused by two distinct and interchangeable signaling formats. Neoplasia 7(4):397-406. Lassman A, Dai C, Fuller GN, Vickers AJ, Holland EC. 2004. Overexpression of c-MYC promotes an undifferentiated phenotype in cultured astrocyts and allows elevated Ras and Akt signaling to induce gliomas from GFAP-expressing cells in mice. Neuron Glia Biology 1(2):157-163. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology www.jax.org/research 10

Janan T. Eppig, Ph.D. Professor The mouse is a key model organism for the understanding of mammalian biology because it has been well studied and is genetically and physiologically similar to humans. To utilize mouse data to its fullest, we have developed an integrated database of mouse genetic, genomic and biological data. The Mouse Genome Informatics Database (MGI) is used by the international scientific community as its primary resource for mouse information and as a tool for new biological discovery. The database contains a wide variety of data pertaining to genes, their DNA and protein sequences, and the phenotypes that result from mutations in different genes. The three central components of MGI are the Mouse Genome Database (MGD), an internationally recognized database for the laboratory mouse, the Mouse Tumor Biology (MTB) database, which facilitates the selection of experimental models for cancer research, and the International Mouse Strain Resource (IMSR), a searchable online database cataloging mouse stocks available worldwide. The database continues to expand to keep abreast of new technologies and to grow with our expanding knowledge of how the genetic blueprint of DNA manifests in traits of a living individual.

Bult CJ, Eppig JT, Blake JA, Kadin JA, Richardson JE; the Mouse Genome Database Group. The Mouse Genome Database: Genotypes, Phenotypes, and Models of Human Disease. Nucleic Acids Res. 2013 Jan 1;41(D1):D885-D891. Heffner CS, Herbert Pratt C, Babiuk RP, Sharma Y, Rockwood SF, Donahue LR, Eppig JT, Murray SA. Supporting conditional mouse mutagenesis with a comprehensive cre characterization resource. Nat Commun. 2012;3:1218. Bello SM, Richardson JE, Davis AP, Wiegers TC, Mattingly CJ, Dolan ME, Smith CL, Blake JA, Eppig JT. Disease model curation improvements at Mouse Genome Informatics. Database (Oxford). 2012 Mar 20;2012:bar063. Eppig JT, Blake JA, Bult CJ, Kadin JA, Richardson JE; Mouse Genome Database Group. The Mouse Genome Database (MGD): comprehensive resource for genetics and genomics of the laboratory mouse. Nucleic Acids Res. 2012 Jan;40(Database issue):D881-6. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology 11 www.jax.org/research

Mary Ann Handel, Ph.D. Senior Research Scientist Our laboratory investigates the genetic regulation of spermatogenesis and male fertility. We focus on meiosis, a specialized cell division unique to germ cells that reduces the number of chromosome sets from two (diploid) to one (haploid), producing the gametes, the eggs and sperm that come together during sexual reproduction. We study the mechanisms by which germ cells form condensed chromosomes as they enter the meiotic division phase. Appropriate dynamics and behavior of chromosomes during meiosis is of crucial importance for the formation of gametes, ensuring the haploid chromosome content of the future gamete, as well as genetic integrity and reproductive success. Our studies are providing significant new information about assembly of mammalian meiotic chromosomes, and ultimately will help us understand how errors in these meiotic mechanisms cause aneuploidy, or inappropriate chromosome number, in offspring. Additionally, we take an unbiased genetic approach to identify new mutations that affect meiotic processes, spermatogenic differentiation, and male fertility. Because the traits we study, spermatogenic “maturation arrest” and fertilization failure, occur in many unexplained cases of human male infertility and reproductive toxicity, this approach can shed light on infertility, and possibly identify potential targets for contraception.

Su YQ, Sun F, Handel MA, Schimenti JC, Eppig JJ. 2012. Meiosis arrest female 1 (MARF 1) has nuage-like function in mammalina oocytes. Proc Natl Acad Sci. 109:18653-18660. Guan Y, Gorenshteyn D, Burmeister M, Wong AK, Schimenti JC, Handel MA, Bult CJ, Hibbs MA, Troyanskaya OG. 2012. Tissue-specific funtional networks for prioritizing phenotype and disease genes. PLoS Comput Biol. 8:e1002694. Jordan PW, Karppinen J, Handel MA. 2012. Polo-like kinase is required for synaptonemal complex disassembly and phosphorylation in mouse spermatocytes. J Cell Sci. 125:5061-5072. Fritsche M, Reinholdt L, Lessard M, Handel MA, Bewersdorf J, Heermann DW. 2012. Entropy-driven spatial organization of synaptonemal complexes within the cell nucleus. PLoS Biol. 7:e36282. Su YQ, Sugiura K, Sun F, Pendola JK, Cox GA, Handel MA, Schimenti JC, Eppig JJ. 2012. MARF1 regulates essential oogenic processes in mice. Science 335:1496-1499. La Salle S, Palmer K, O’Brien M, Schimenti JC, Eppig JJ, Handel MA. 2012. Spata22, a novel vertebrate-specific gene, is required for meiotic progress in mouse germ cells. Bio Reprod. 86:1-12. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology www.jax.org/research 12

David E. Harrison, Ph.D. Professor The Harrison research group has two focus areas, as detailed on our lab site— . https://ra.jax.org/faculty/ harrison/,DanaInfo=research.jax.org+index.html Under “Gerontology: Mechanisms of Aging” we investigate aging in mouse models, focusing on processes that have the potential to retard aging and prolong health. For example, one line of research investigates ways to delay aging using drugs such as rapamycin, mutations that reduce IGF-1/ insulin pathway function, and a diet restriction that retains insulin resistance and obesity. To increase life span, development of cancer must be delayed. We test physiological and genomic mechanisms that increase lifespan in various models, and develop methods to extend benefits from animal models to the clinic. Under “Hematology: Stem Cells” we work on hematopoietic stem cells (HSCs) and other adult stem cells, which constantly proliferate and differentiate to maintain tissue functions throughout life. If aging exhausts the function of adult stem cells, the balance between damage and repair is disrupted and tissue functions become defective. We defined strain differences in HSC aging, and test mechanisms that protect stem cells from aging. Aging in cardiac and mesenchymal stem cells is less well defined, and we are developing models for their study in vivo to test if they show the same strain differences as HSC.

Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors M, Fernandez E, Miller RA. 2009. Rapamycin fed from 20 months of age extends lifespan in genetically heterogeneous mice. Nature. 460:392-395. Flurkey K, Astle CM, Harrison DE. 2010. Life Extension by Diet Restriction and N-Acetyl-L-Cysteine in Genetically Heterogeneous HET3 Mice. J Gerontol A Biol Sci Med Sci. 65(12):1275-84. Flurkey K, Harrison DE. 2010. Reproductive ageing: Of worms and women. Nature Nov18(468):386-7 Yuan R, Flurkey K, Meng Q, Astle CM, Harrison DE. 2012. Genetic regulation of lifespan, metabolism and body weight in Pohn, a new wild-derived mouse strain. J Gerontol A Biol Sci Med Sci 68(1):27-35. Zhang EY, Xiong Q, Ye L, Suntharalingam P, Wang X, Astle CM, Zhang J, Harrison DE. 2012. Fetal myocardium in the kidney capsule: an in vivo model of repopulation of myocytes by bone marrow cells. PLoS One 7(2):e31099 Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology 13 www.jax.org/research

Gareth Howell, Ph.D. Assistant Professor In the Howell lab, we apply genetics and genomics approaches to identify fundamental processes involved in the initiation and early propagation of age-related neurodegenerative diseases, focusing on Alzheimer’s disease, non-Alzheimer’s dementia and glaucoma. Understanding these processes provides the greatest opportunity of therapeutic intervention. We are particularly interested in the role of non-neuronal cells including astrocytes, monocyte-derived cells (such as microglia), endothelial cells and pericytes. In previous work, I applied novel genomics and bioinformatics strategies to identify new molecular stages of glaucoma that preceded morphological changes. Genetic knockout and/or pharmaceutical approaches showed that targeting the Complement cascade and Endothelin system significantly lessened glaucomatous neurodegeneration in mice. Our work with glaucoma continues in collaboration with Dr. Simon John, and we are also now applying similar genetics and genomics strategies to understand initiating and early stages of Alzheimer’s disease, Vascular Dementia and other dementias. A major aim is to combine knowledge from human genetic studies with the strengths of mouse genetics to develop new and improved mouse models for dementias and make them readily available to the scientific community.

Reinholdt LG, Howell GR, Czechanski AM, Macalinao DG, MacNicoll KH, Lin CS, Donahue LR, John SWM. 2012. Generating embryonic stem cells from the inbred mouse strain DBA/2J, a model of glaucoma and other complex diseases. PLoS ONE G2012;7(11):e50081. Simon MM, Mallon AM, Howell GR, Reinholdt LG. 2012. High throughput sequencing approaches to mutation discovery in the mouse. Mamm Genome 23(9-10):499-513. Howell GR, Soto I, Zhu X, Ryan M, Macalinao DG, Sousa GL, Caddle LB, Harmon K, Barbay JM, Porciatti V, Anderson MG, Smith RS, Clark AF, Libby RT, John SWM. 2012. Radiation treatment inhibits monocyte entry into the optic nerve head and prevents glaucoma in DBA/2J mice. J Clin Invest 122(4):1246-1261. Howell GR, Macalinao DR, Sousa G, Walden M, Soto I, Kneeland S, Barbay J, King BL, Marchant JK, Hibbs M, Stevens B, Barres BA, Clark AF, Libby RT, John SWMJ . 2011. Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. 121(4):1429-44. J Clin Invest 121(4):1429-1444. Howell GR, Libby RT, Jakobs TC, Smith RS, Phalan FC, Barter JW, Barbay JM, Marchant JK, Mahesh N, Porciatti V, Whitmore AV, Masland RH, John SW. 2007. Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma. J Cell Biol. 179:1523-37. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology www.jax.org/research 14

Simon John, Ph.D. Professor Our research investigates the molecular features of complex diseases that lead to the death of neural cells (neurodegenerations). Most of our projects focus on glaucoma. Glaucoma is a major cause of human blindness and is often associated with elevated pressure within the eye itself (intraocular pressure, or IOP). The harmfully high pressure damages retinal ganglion cells (RGCs) resulting in a pressure-induced neurodegeneration. We use mouse models to study glaucoma. We combine genetics with genomics, cell/molecular biology and physiology to understand glaucoma. We are identifying new genes and pathways that cause glaucoma. We study how abnormal ocular development and other processes lead to high IOP and glaucoma and are determining how high intraocular pressure damages retinal neurons. We are also investigating possible treatments and are currently experimenting with a new radiation treatment we discovered that completely prevents glaucomatous neurodegeneration in the vast majority of treated animals.

Reinholdt LG, Howell GR, Czechanski AM, Macalinao DG, MacNicoll KH, Lin CS, Donahue LR, John SWM. 2012. Generating embryonic stem cells from the inbred mouse strain DBA/2J, a model of glaucoma and other complex diseases. PLoS ONE G2012;7(11):e50081. Zhu X, Libby RT, deVries WN, Smith RS, Wright DL, Bronson RT, Seburn KL, John SWM. 2012. Mutations in a P-type ATPase gene cause axonal degeneration. Plos Genet 8(8):e1002853. McDowell CM, Luan T, Zhang Z, Putliwala T, Wordinger RJ, Millar JC, John SWM, Pang IH, Clark AF. 2012. Mutant human myocilin induces strain specific differences in ocular hypertension and optic nerve damage in mice. Exp Eye Res 100:65-72 Howell GR, Soto I, Zhu X, Ryan M, Macalinao DG, Sousa GL, Caddle LB, MacNicoll KH, Barbay JM, Porciatti V, Anderson MG, Smith RS, Clark AF, Libby RT, John SWM. 2012. Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma. J Clin Invest 122(4):1246-61 Fernandes KA, Harder JM, Fornarola LB, Freeman RS, Clark AF, Pang IH, John SWM, Libby RT. 2012. JNK2 and JNK3 are major regulators of axonal injury- induced retinal ganglion cell death. Neurobiol Dis 46(2):393-401 Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology 15 www.jax.org/research

Kenneth R. Johnson, Ph.D. Associate Professor The overall goals of our research program are to identify molecules and pathways that are important in the development and physiology of the ear. We study mouse mutations that disrupt these processes and develop these mutations as models of human deafness disorders and age-related hearing loss. We have established a screening program to identify inbred and mutant mice with hearing impairment, which we assess by auditory brainstem response (ABR) analysis. In collaboration with colleagues we identified the first known gene in the mouse to cause age-related hearing loss (AHL), the most common type of human hearing impairment. We have mapped gene loci that contribute to AHL and are now refining their map positions as well as testing candidate genes that may underlie these effects. Our research team is also investigating new mouse mutations that cause hearing impairment. By identifying the genes underlying these mutations and studying their functions, we hope to gain a better understanding of the molecular mechanisms involved in the auditory process. The mutant mice also provide valuable models for studying human non‑syndromic deafness disorders and human syndromes with associated deafness.

Johnson KR, Longo-Guess CM, Gagnon LH. 2012. Mutations of the mouse ELMO domain containing 1 gene (Elmod1) link small GTPase signaling to actin cytoskeleton dynamics in hair cell stereocilia. PLoS One. 7:e36074. Kane KL, Longo-Guess CM, Gagnon LH, Ding D, Salvi RJ, Johnson KR. 2012. Genetic background effects on age-related hearing loss associated with Cdh23 variants in mice. Hear Res. 283:80-88. Fang Q, Longo-Guess C, Gagnon LH, Mortensen AH, Dolan DF, Camper SA, Johnnson KR. 2011. A modifier gene alleviates hypothyroidism-induced hearing impairment in Pou1f1dw dwarf mice. Genetics. 189:665-673. Shin B-B, Longo-Guess CM, Gagnon LH, Saylor KW, Dumont RA, Spinelli KJ, Pagana JM, Wilmarth PA, David LL, Gillespie PG, Johnson KR. 2010. The R109H variant of fascin-2, a developmentally regulated actin crosslinker in hair- cell stereocilia, underlies early-onset hearing loss of DBA/2J mice. J Neurosci 30:9683-9694. Johnson KR, Yu H, Ding D, Jiang H, Gagnon LH, Salvi RJ . 2010. Separate and combined effects of Sod1 and Cdh23 mutations on age-related hearing loss and cochlear pathology in C57BL/6J mice. Hear Res 268:85-92. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology www.jax.org/research 16

Ron Korstanje, Ph.D. Assistant Professor Renal aging is associated with a decline in renal function, including decreased glomerular filtration rate and reduced sodium homeostasis. These impairments result from morphological changes that affect glomeruli, tubuli and interstitium. Declining kidney function may lead to chronic kidney disease, a major health problem, especially regarding the growing geriatric population. Currently 10% of the US population has chronic kidney disease and more than half a million people are on dialysis. Different pathways seem to play a role in age-related kidney damage. A general cause is unknown, but genetic background seems to play an important role. The mouse is an excellent model for mammalian genetic studies, and the methods for identifying genes involved in many disease phenotypes have become extremely sophisticated. Mice can be kept in controlled environments, thereby reducing the environmental variation. Also, mice and their kidneys can be easily manipulated to mimic disease conditions (e.g. diabetes, hypertension, and ischemia-reperfusion). Finally, candidate genes can be manipulated in the mouse through knockout (complete or conditional), knockdown (siRNA) of gene expression, and overexpression (transgenesis). We identified several loci and novel candidate genes for renal function and renal damage. Several of these loci have now been associated with kidney function in human genome-wide association studies and we are currently determining their role in the disease process in both zebrafish and mouse models.

Hageman RS, Leduc MS, Caputo C, Tsaih SW, Churchill GA, Korstanje R (2011) Uncovering Genes and Regulatory Pathways Related to Urinary Albumin Excretion in Mice. Journal of the American Society of Nephrology 22(1):73-81. Garret M, Pezzolesi M, Korstanje R (2010) Integrating human, rat, and mouse data to identify the genetic factors involved in chronic kidney disease. Journal of the American Society of Nephrology 21(3):398-405. Tsaih S, Pezzolesi M, Yuan R, Warram JH, Krolewski A, Korstanje R (2010) Genetic analysis of albuminuria in the aging mouse. Kidney International 77(3):201-210. Doorenbos C, Tsaih S, Sheehan S, Ishimori N, Navis G, Churchill G, DiPetrillo K, Korstanje R. (2008) Quantitative Trait Loci for urinary albumin in crosses between C57BL/6J and A/J inbred mice in the presence and absence of Apoe. Genetics 179:693-699. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology 17 www.jax.org/research

Vivek Kumar, Ph.D. Assistant Professor The Kumar Lab studies neural circuits in the brain whose misregulation leads to behavioral abnormalities including addiction, attention deficit and hyperactivity disorder, and depression. Using mouse molecular genetics as foundation, and a combination of biochemistry, physiology, and imaging techniques we dissect these complex behaviors in mammals. We use two functional genomics approaches in mice - forward genetic ethylnitrosourea (ENU) mutagenesis screens and quantitative trait loci (QTL) analysis - to identify genes and pathways that regulate these behaviors. Powerful and unbiased, forward genetic approaches make no a priori assumptions and only require a clear well-defined assay for gene discovery. We have used high-throughput screening pipeline to discover mutants for cocaine response and open field behavior. Using physical mapping followed by next generation sequencing we have identified novel genes and alleles that regulate cocaine response and anxiety related behaviors.

Kumar V, Kim K, Joseph C, Kourrich S, Yoo SH, Huang HC, Vitaterna MH, Pardo- Manuel de Villena F, Churchill G, Bonci A, Takahashi JS. 2013. C57BL/6N mutation in Cytoplasmic FMRP interacting protein 2 (Cyfip2) regulates cocaine response. Science 342: 1508-1512. Kumar V, Andersen B, Takahashi JS. 2013. Epidermal stem cells ride the circadian wave. Genome Biology 14: 140-143. Shimomura K, Kumar V, Koike N, Kim TK, Chong J, Buhr ED, Whiteley AR, Low SS, Omura C, Fenner D, Owens JR, Richards M, Yoo SH, Hong HK, Vitaterna MH, Bass J, Pletcher MT, Wiltshire T, Hogenesch JB, Lowrey PL, Takahashi JS. 2013. Usf1, a suppressor of the circadian clock mutant, reveals the nature of the DNA-binding of the CLOCK:BMAL1 complex in mice. E-Life 2:e00426. Yoo SH, Mohawk JA, Siepka SM, Shan Y, Huh SK, Hong HK, Kornblum I, Kumar V, Koike N, Xu M, Nussbaum J, Liu X, Chen Z, Chen ZJ, Green CB, and Takahashi JS. 2013. Competing E3 Ubiquitin Ligases Govern Circadian Periodicity by Degradation of CRY in Nucleus and Cytoplasm. Cell 152(5): 1091-1105. Koike N, Yoo SH, Huang HC, Kumar V, Lee C, Kim TK, Takahashi JS. 2012. Transcriptional Architecture and Chromatin Landscape of the Core Circadian Clock in Mammals. Science 338(6105): 349-354. Geyfman M, Kumar V, Liu Q, Ruiz R, Gordon W, Espitia F, Cam E, Millar SE, Smyth P, Ihler A, Takahashi JS, Andersen B. 2012. Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis. PNAS 109(29):11758-63 Kumar V, Kim K, Joseph C, Thomas LC, Hong HK, and Takahashi JS. 2011. A Second Generation High Throughput Forward Genetic Screen in Mice to Isolate Subtle Behavioral Mutants. PNAS 108: Sup 3 15557-15564. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology www.jax.org/research 18

Steve Munger, Ph.D. Associate Professor The genetic origins of most developmental disorders and diseases are complex and remain poorly understood. Rather than a single deleterious mutation, genetic susceptibility to common diseases is conferred by many variants that indi vidually assert subtle effects but in certain combinations perturb cellular networks sufficiently to bias them to a disordered/diseased state. Classic single-gene experimental approaches fail to elucidate these interactions, but new integrative genomic and genetic approaches from the emerging field of “Systems Genetics” hold considerable promise. The Munger lab combines experimental and computational methods with advanced mouse mapping populations to solve these complex genetic puzzles. We examine the natural genetic variation driving individual differences in 1) susceptibility to sex reversal during primary sex determination of the gonad, 2) disease severity in a mouse model of Cornelia de Lange Syndrome, and 3) transcript and protein expression in the adult liver. We apply our genetic and genomics toolkit to predict causal variants and genetic interactions underlying phenotypic variability, validate these predictions at the bench with functional genomics methods, and ultimately seek to extend these results to inform patient diagnosis and treatment. The Munger lab strives to be an open, collaborative, diverse, and supportive scientific environment, and I am committed to providing graduate students and post-doctoral fellows with the interdisciplinary training necessary to be successful independent scientists in the genomic era.

Chick JM*, Munger SC*, Simecek P, Huttlin EL, Choi KB, Gatti DM, Raghupathy N, Svenson KL, Churchill GA, and Gygi SP. Defining the consequences of genetic variation on a proteome-wide scale. In revision at Nature. *Equal contributors. Munger SC, Raghupathy N, Choi K, Simons AK, Gatti DM, Hinerfeld DA, Svenson KL, Keller MP, Attie AD, Hibbs MA, Graber JH, Chesler EJ, and Churchill GA. 2014. RNA-seq alignment to individualized genomes improves transcript abundance estimates in multiparent populations. GENETICS, 198(1): 59-73. Munger SC*, Natarajan A*, Looger LL, Ohler U, and Capel B. 2013. Fine timecourse expression analysis reveals cascades of activation and repression and maps a regulator of mammalian sex determination. PLoS Genetics, 9(7): e1003630. * Equal contributors. Churchill GA, Gatti DM, Munger SC, and Svenson KL. 2012. The diversity outbred mouse population. Mammalian Genome, 23(9-10): 713-718. Munger SC and Capel B. 2012. Sex and the circuitry: Progress toward a systems- level understanding of vertebrate sex determination. Wiley Interdisciplinary Reviews – Systems Biology and Medicine, doi: 10.1002/wsbm. 1172. Munger SC, Aylor DL, Syed HA, Magwene PM, Threadgill DW, and Capel B. 2009. Elucidation of the transcription network governing mammalian sex determination by exploiting strain-specific susceptibility to sex reversal.Genes & Development, 23:

Juergen K. Naggert, Ph.D. Professor The primary cilium is the sensory organ and signaling organizing center of the cell. It consists of a specialized cell membrane extrusion at the surface of the cell to which active signaling receptors localize, a ciliary axoneme that provides a scaffold for protein trafficking, and a basal body that serves as the ciliums’ and the cells’ microtubule organizing center. Defects in the protein constituents of the primary cilium and its associated structures give rise to a multitude of diseases that are collectively called ciliopathies. Because of its diverse functions, the cilium also plays a role in many common diseases such as obesity, diabetes, kidney disease and retinal degeneration. Our lab currently investigates the roles of the Alström Syndrome protein, the tubby gene family, and meckelin in cilia biogenesis and function using genetic and biochemical approaches.

Collin GB, Marshall JD, King BL, Milan G, Maffei P, Jagger DJ, Naggert JK. 2012. The Alstrom syndrome protein, ALMS1, interacts with alpha-actinin and components of the endosome recycling pathway. PLoS One 7: e37925. Maddox DM, Ikeda S, Ikeda A, Zhang W, Krebs MP, Nishina PM, Naggert JK. 2012. An allele of microtubule-associated protein 1A (Mtap1a) reduces photoreceptor degeneration in Tulp1 and Tub Mutant Mice. Invest Ophthalmol Vis Sci 53: 1663-1669. Collin GB, Won J, Hicks WL, Cook SA, Nishina PM, Naggert JK. 2012. Meckelin is necessary for photoreceptor intraciliary transport and outer segment morphogenesis. Invest Ophthalmol Vis Sci 53: 967-974. Marshall JD, Maffei P, Collin GB, Naggert JK. 2011. Alstrom syndrome: genetics and clinical overview. Curr Genomics 12: 225-235. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology www.jax.org/research 20

Patsy M. Nishina, Ph.D. Professor Dr. Nishina focuses on the identification of common pathways that lead to disease and that are impacted by primary mutations. Her laboratory has participated in the identification of the molecular bases of many neurological mutants (i.e. primary mutations) that have been used as new entry points for understanding normal retinal function. The Nishina lab is particularly interested in molecules important in the development, function and maintenance of: 1) retinal pigmented epithelial cells, 2) the extracellular matrix, 3) photoreceptor outer segments, and 4) Müller glial cells and astrocytes. While the main approach of Dr. Nishina’s program continues to be discovery research using genetical studies; marker analyses, functional, biochemical, genomic and proteomic studies are additional approaches used to elucidate the function and pathways through which retinal molecules act. Additionally, to identify entries into pathways, new models are generated through genetic engineering and screening of chemically mutagenized mice.

Edwards MM, Mammadova-Bach E, Alpy F, Klein A, Hicks WL, Roux MJ, Simon-Assmann P, Smith RS, Orend G, Wu J, Peachey NS, Naggert JK, Lefebvre O, Nishina PM. 2010. Mutations in Lama1 disrupt retinal vascular development and inner limiting membrane formation. J Biol Chem 285:7697-7711. Lee Y, Smith RS, Jordan W, King BL, Won J, Valpuesta JM, Naggert JK, Nishina PM. 2010. Prefoldin 5 is required for normal sensory and neuronal development in a murine model. J Biol Chem 286:726-736. Boldt K, Mans DA, Won J, van Reeuwijk J, Vogt A, Kinkl N, Letterboer SJ, Hicks WL, Hurd RE, Naggert JK, Texier Y, den Hollander AI, Koenekoop RK, Bennett J, Cremers FP, Gloeckner CJ, Nishina PM, Roepman R, Ueffing M. 2011. Disruption of intraflagellar protein transport in photoreceptor cilia causes Leber congenital amaurosis in humans and mice. J Clin Invest 121:2169- 2180. Won J, Marin de Evsikova C, Smith RS, Hicks WL, Edwards MM, Longo- Guess C, Li T, Naggert JK, Nishina PM. 2011. NPHP4 is necessary for normal photoreceptor ribbon synapse maintenance and outer segment formation and for sperm development. Hum Mol Genet 20:482-496. Collin GB, Won J, Hicks WL, Cook SA, Nishina PM, Naggert JK. 2012. Meckelin is necessary for photoreceptor intraciliary transport and outer segment morphogenesis. Invest Ophthalmol Vis Sci 53:967-974. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology 21 www.jax.org/research

Kenneth Paigen, Ph.D. Professor DNA serves as the substrate for three biological processes: replication, genetic recombination and gene transcription. Our group is presently concerned with the latter two, exploring the mechanisms that determine the location of genetic recombination sites and the extent to which the physical organization of genes along chromosomes is related to their biological function. We have now begun identifying and characterizing the components of a novel regulatory system controlling the location of recombination hotspots, the sites of genetic recombination and the extent to which recombination is regionally controlled and differs between the sexes. Analyzing the relation between gene function and location, we find that the persistence of ancient gene duplications keeping functionally related genes in proximity is the dominant factor determining genome organization.

Paigen K, Petkov P. 2012. Meiotic DSBs and the control of mammalian recombination. Cell Res 22(12):1624-1626. Commentary Walker M, King B, Paigen K. 2012. Clusters of ancestrally related genes that show paralogy in whole or in part are a major feature of the genomes of humans and other species. PLoS One 7(4):e35274. 3 Paigen K, Petkov P. 2010. Mammalian recombination hotspots: properties, control and evolution. Nat Genet Rev 11:221-233 (Review). Parvanov ED, Petkov PM, Paigen K. 2010. Prdm9 controls activation of mammalian recombination hotspots. Science 327(5967):835. Petkov, P. M., K. W. Broman, et al. (2007). Crossover interference underlies sex differences in recombination rates.Trends Genet 23(11): 539-42. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology www.jax.org/research 22

Luanne Peters, Ph.D. Professor Our research focuses on blood formation, or hematopoiesis, with a major emphasis on red blood cell formation (erythropoiesis). We use the mouse as a model system to elucidate the genetic basis of human disease. We study both single gene (Mendelian) defects and complex, polygenic phenotypes that arise from natural genetic variation. Current projects are focused on four major areas. First is the identification and functional characterization of gene defects in mice carrying spontaneous, genetically engineered, or chemically induced mutations causing inherited anemia. A second focus, which is highly relevant to sickle cell anemia, is the identification of genetic loci regulatingβ -like globin switching using unbiased genetic (QTL mapping) and genomic (RNA- seq, ChIP-seq) approaches. A third major project focuses on analysis of aberrant Ras signaling and function in blood formation. Finally, we are studying the role of natural genetic variation among inbred strains of mice in determining baseline peripheral blood values, which are known risk factors for sickle cell disease severity, stroke, cardiovascular disease, and all-cause mortality.

Blanc L, Ciciotte SL, Gwynn B, Hildick-Smith GJ, Pierce EL, Soltis KA, Cooney JD, Paw BH, Peters LL. 2012. Critical function for the Ras-GTPase Activating Protein RASA3 in vertebrate erythropoiesis and megakaryopoiesis. Proc Natl Acad Sci USA 109, 12099-12104 Peters LL, Shavits JA, Lambert AJ, Tsaih SW, Li Q, Su Z, Leduc MS, Paigen B, Churchill GA, Ginsburg D, and Brugnara, C. 2010. Sequence variation at multiple loci influence red cell hemoglobin content.Blood 116, e139-149. Siatecka M, Sahr KE, Andersen SG, Mezei M, Bieker JJ, Peters LL. 2010. Severe anemia in the Nan mutant mouse caused by sequence-selective disruption of erythroid Kruppel-like factor. Proc Natl Acad Sci USA 107, 15151-15156. Robledo RF, Lambert AJ, Cirlan M, Cirlan AF, Campagna DR, Lux SE, Peters LL. 2010. Analysis of novel sph (spherocytosis) alleles in mice reveals allele- specific loss of band 3 and adducin inα -spectrin deficient red cells. Blood 115, 1804-1814. Robledo RF, Ciciotte SL, Gwynn B, Sahr KE, Gilligan DM, Peters LL. 2008. Targeted deletion of α-adducin results in absent β- and γ-adducin, compensated hemolytic anemia, and lethal hydrocephalus in mice. Blood 112, 4298-4307. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology 23 www.jax.org/research

Derry C. Roopenian, Ph.D. Professor The overall goals of our laboratory are to understand why the immune system causes autoimmune diseases and to devise methods to predict and treat them. We develop and use mouse strains that provide models for human diseases such as lupus, rheumatoid arthritis, and epidermolysis bullosa. We use a combination of genetics, molecular biological and cellular immunological tools to dissect the molecular and cellular processes that cause these diseases. Finally, we study the mechanisms that affect the persistence of antibodies and antibody-based therapeutics. The information gained from all of these approaches is then used to devise possible therapeutic approaches with a keen eye on those that can be translated to humans.

Andersen JT, Foss S, Kenoanova VE, Olafesen T, Leikfoss IS, Roopenian DC, Wu AM, Sandie I. 2012. Anti-carcinoembryonic antigen single-chain variable fragment antibody variants bind mouse and human neonatal Fc receptor with differen t affinities that reveal distinct cross-species differences in serum half- life. J Biol Chem Jun 29:287(27):22927-37. Sproule TJ, Roopenian DC, Sundberg JP. A direct method to determine the strength of the dermal-epidermal junction in a mouse model for epidermolysis bullosa. Exp Dermatol. 2012 Jun;21(6):453-5. Epub 2012 Apr 16. Christianson GJ, Sun VZ, Akilesh S, Pesavento E, Proetzel G, Roopenian DC. Monoclonal antibodies directed against human FcRn and their applications. MAbs. 2012 Mar 1;4(2). Ryu SJ, Jeon JY, Chang J, Sproule TJ, Roopenian DC, Choi EY. A single-amino- acid variant of the H60 CD8 epitope generates specific immunity with diverse TCR recruitment. Mol Cells. 2012 Apr;33(4):393-9. McPhee CG, Duncan FJ, Silva KA, King LE Jr, Hogenesch H, Roopenian DC, Everts HB, Sundberg JP. Increased expression of Cxcr3 and its ligands, Cxcl9 and Cxcl10, during the development of alopecia areata in the mouse. J Invest Dermatol. 2012 Jun;132(6):1736-8. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology www.jax.org/research 24

Nadia Rosenthal Ph.D. FMedSci FAAHMS Scientific Director

Professor The Rosenthal laboratory uses mammalian genetics to explore the embryonic development of heart and skeletal muscle and the regeneration of adult tissues. We employ molecular genetic strategies to investigate mechanisms of development, disease, and tissue regeneration. Our research focuses on the role of growth factors, stem cells and the immune system in the resolution of tissue injury for application to regenerative medicine, and has led to significant advances in novel cell-based therapies for muscle and heart aging and disease. Research in the Rosenthal group concentrates on embryonic heart development, aging mechanisms and stem cell-driven regeneration of neuromuscular and cardiac tissue, using the mouse as a model for human response to disease. Our studies are designed to define the common nodal points of signaling in regenerative processes and the role played by the immune response in controlling inflammation and promoting tissue repair.

Sattler S, Rosenthal N. The neonate versus adult mammalian immune system in cardiac repair and regeneration. Biochim Biophys Acta. 2016Jan 20. Pii: S0167- 4889(16)30001-5. doi: 10.1016/j.bbamcr.2016.01.011. Gallego-Colon E, Sampson RD, Sattler S, Sarathchandra P, Schneider MD, Rosenthal N, Tonkin J. Cardiac-restricted IGF-1Ea overexpression reduces the early accumulation of inflammatory myeloid cells and mediates expression of extracellular matrix remodelling genes after acute myocardial infarction. Mediators of Inflammation, 2015:484357. doi: 10.1155/2015/484357. Epub 2015 Sep 30. Tonkin J, Temmerman T, Sampson RD, Colon EG, Barberi L, Bilbao D, Schneider MD, Musarò A, Rosenthal N. Monocyte/macrophage-derived IGF-1 orchestrates murine skeletal muscle regeneration and modulates autocrine polarization. Molecular Therapy 2015, 23:1189-200. Pinto AR, Ilinykh A, Ivey MJ, Kuwabara JT, D’Antoni M, Debuque RJ, Chandran A, Wang L, Arora K, Rosenthal N, Tallquist MD. Revisiting Cardiac Cellular Composition. Circ Res. 2015 Dec 3. doi:pii: CIRCRESAHA.115.307778. [Epub ahead of print] Godwin J, Kuraitis D, Rosenthal N. Extracellular matrix considerations for scar-free repair and regeneration: Insights from regenerative diversity among vertebrates. Int J Biochem Cell Biol. 2014 56C:47-55. Bilbao D, Luciani L, Johannesson B, Piszczek A, Rosenthal N. Insulin-like growth factor-1 stimulates regulatory T cells and suppresses autoimmune disease. EMBO Mol Med. 2014 Oct 22;6(11):1423-35. doi: 10.15252/emmm.201303376. Forbes SJ, Rosenthal N. Preparing the ground for tissue regeneration: from mechanism to therapy. Nat Med. 2014 Aug;20(8):857-69. doi: 10.1038/nm.3653. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology 25 www.jax.org/research

David V. Serreze, Ph.D. Professor Our laboratory investigates the genetic control mechanisms allowing the immune system to recognize and destroy foreign pathogens, but not normal constituents of the body. Defects in these mechanisms underlie many autoimmune diseases, including type 1 (juvenile onset, insulin dependent) diabetes. Using NOD (non-obese diabetic) inbred mice, we focus on the process through which genes that normally elicit immune responses to foreign intruders can sometimes trigger autoimmune responses against the body’s own cells, such as the pancreatic cells that make insulin. We have shown that some genes play a role in type 1 diabetes even when they do not contain deleterious mutations. Instead they are normal genes that only contribute to type 1 diabetes pathology when collected together in a specific fashion. We are also investigating defects in the differentiation of a particular type of leukocyte in NOD mice that subsequently allows for the development of autoimmune responses. This work may help identify the mechanisms and compounds that normally prevent autoimmunity, and hence reveal strategies for pharmacological interventions in humans at risk for type 1 diabetes.

Niens M, Grier AE, Marron M, Greiner DL, and Serreze DV. Prevention by multi-peptide coupled-cells of “humanized” diabetogenic CD8 T-cell responses in HLA transgenic NOD mice. Diabetes, 60:1229, 2011. Driver JP, Chen Y-G, Zhang W, Asrat S, and Serreze DV. Unmasking genes in a type 1 diabetes resistant mouse strain that enhance the peripheral activation of pathogenic CD8 T-cells. Diabetes, 60:1354, 2011. Serreze DV, Chapman HD, Niens M, Dunn R, Driver JP, Haller M, Wasserfall C, and Atkinson MA. Loss of intra-islet CD20 expression may complicate efficacy of B-lymphocyte directed type 1 diabetestherapies.Diabetes , 60:2914, 2011. Chen Y-G, Tsaih S-W, and Serreze DV. Genetic control of murine invariant natural killer T-cell development dynamically differs dependent on the examined tissue type. Genes and Immunity, 13:164, 2012. Wekerle H, Flugel A, Fugger L, Schett G, and Serreze D. Autoimmunity’s next top models. Nature Medicine, 18:66, 2012. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology www.jax.org/research 26

Leonard D. Shultz, Ph.D. Professor A fundamental understanding of many biological processes has stemmed from experimental studies using animal models. Genetically-defined laboratory mice are used as models for many human diseases and also as hosts for human cells and tissues. Our laboratory has a long history of studying spontaneous mutations that disrupt the hematopoietic or immune systems or cause other pathologic changes of interest to our lab members. Single gene mutations currently under study encompass immunodeficiency, autoimmunity, thrombocytopenia, cardiomyopathy, renal disease, diabetes, and wound healing. These investigations seek to identify the molecular basis of the disease under study as well as determining underlying mechanisms at the cellular and biochemical levels. In order to directly study development and function of human cells and tissues in normal and disease states we have developed, optimized, and validated an expanding panel of immunodeficient mouse models termed “humanized mice”. There is a growing need for these animal models to carry out in vivo studies on human cells and tissues without putting individuals at risk. We are developing next generation humanized mouse models that support heightened levels of engraftment with normal and malignant human cells and tissues. Our research has leveraged these humanized mouse models for translational studies on human hematopoiesis, immunity, diabetes, regenerative medicine, transplantation tolerance and cancer.

Chase TH, Lyons BL, Bronson RT, Foreman O, Donahue LR, Burzenski LM, Gott B, Lane P, Harris B, Ceglarek U, Thiery J, Wittenburg H, Thon JN, Italiano JE, Jr., Johnson KR, Shultz LD. 2010. The mouse mutation “thrombocytopenia and cardiomyopathy” (trac) disrupts Abcg5: a spontaneous single gene model for human hereditary phytosterolemia/sitosterolemia. Blood 115: 1267-1276. Saito Y, Uchida N, Tanaka S, Suzuki N, Tomizawa-Murasawa M, Sone A, Najima Y, Takagi S, Aoki Y, Wake A, Taniguchi S, Shultz LD, Ishikawa F. 2010. Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nat Biotechnol 28: 275-280. Shultz LD, Saito Y, Najima Y, Tanaka S, Ochi T, Tomizawa M, Doi T, Sone A, Suzuki N, Fujiwara H, Yasukawa M, Ishikawa F. 2010. Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2r gamma(null) humanized mice. Proc Natl Acad Sci U S A 107: 13022-13027. Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL. 2012. Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol 12: 786-798. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology 27 www.jax.org/research

John P. Sundberg, D.V.M., Ph.D., Diplomate, A.C.V.P. Professor There is an old saying that “pathology is the mother of medicine.” Diseases, and more specifically the discipline of studying diseases (pathology), are why we have medicine and biomedical research. Correctly identifying a disease and the various processes each disease undergoes as it develops is the basis of most work done at The Jackson Laboratory. Through a collaborative effort of scientists in our Jackson Aging Center, we are identifying strain specific diseases in 31 heavily used inbred strains of mice and using modern bioinformatic technologies are identifying the genes responsible for many of these diseases, including for many types of cancer. As humans get similar diseases as they age, this information will be vitally important to studying complex genetic diseases associated with aging. Alopecia areata, a cell mediated autoimmune disease featuring hair loss, is a long-term focus of our laboratory group. We have identified over 50 genes involved with this complex disease including one that, 10 years after the discovery in mice was confirmed in human patients and is now the focus of drug trials. We also work on projects investigating chronic proliferative dermatitis due to a mutation in the mouse Sharpin gene, which regulates NFKB and inflammation, numerous mouse models for cicatricial (scarring alopecia), as well as characterizing mutant mice with hair abnormalities which help us define novel molecular pathways involved in normal and abnormal skin biology.

Berndt A, Li Q, Potter CS, Liang Y, Silva KA, Kennedy V, Uitto J, Sundberg JP. 2012. A Single-Nucleotide Polymorphism in the Abcc6 Gene Associates with Connective Tissue Mineralization in Mice Similar to Targeted Models for Pseudoxanthoma Elasticum. J Invest Dermatol, in press, doi: 10.1038/jid.2012.340 Everts HB, Silva KA, Montgomery S, Suo L, Menser M, Valet AS, King LE, Ong DE, Sundberg JP. 2012. Retinoid Metabolism Is Altered in Human and Mouse Cicatricial Alopecia. J Invest Dermatol, in press, doi: 10.1038/jid.2012.393 McPhee CG, Duncan FJ, Silva KA, King LE, Jr., Hogenesch H, Roopenian DC, Everts HB, Sundberg JP. 2012. Increased Expression of Cxcr3 and its Ligands, Cxcl9 and Cxcl10, During the Development of Alopecia Areata in the Mouse. J Invest Dermatol 132: 1736-1738. Rice RH, Bradshaw KM, Durbin-Johnson BP, Rocke DM, Eigenheer RA, Phinney BS, Sundberg JP. 2012. Differentiating Inbred Mouse Strains from Each Other and Those with Single Gene Mutations Using Hair Proteomics. PLoS One 7: e51956. Schofield PN, Vogel P, Gkoutos GV, Sundberg JP. 2012. Exploring the Elephant: Histopathology in High-Throughput Phenotyping of Mutant Mice. Dis Model Mech 5: 19-25. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology www.jax.org/research 28

Basile Tarchini, Ph.D. Assistant Professor Fundamental to our interaction with the world, hearing is first encoded by epithelial hair cells in the inner ear. These mechanosensory cells transform the sound- induced deflection of movement detectors protruding at the apical surface into electrical impulses relayed to the brain. Our research goals are to unravel the molecular mechanisms shaping hair cells for perception. Sensory ability requires striking polarization of the cytoskeleton at multiple levels during development. In the epithelial plane, we recently showed that polarized exclusion of microvilli frames the V-shaped bundle they form in individual cells. Across neighboring cells, V-shaped bundles adopt a uniform orientation, a property known as “planar cell polarity.” Orthogonal to the epithelial plane, microvilli grow into stereocilia of graded heights, forming the staircase-like mechanosensory organ of the cell. How are these distinct levels of cytoskeleton polarity implemented and interconnected? Understanding where morphogenesis meets function will not only add to our understanding of hereditary hearing loss and suggest potential treatments, but it will also be critical for achieving hair cell regeneration after injury, a fascinating property of lower vertebrates lost in mammals.

Tarchini B (*), Jolicoeur C, Cayouette M. 2013. A molecular blueprint at the apical surface establishes planar asymmetry in cochlear hair cells. Developmental Cell 27, 88-102. (*) is a corresponding author Alsio JM, Tarchini B, Cayouette M, Livesey FJ. 2013. Ikaros promotes early- born neuronal fates in the cerebral cortex. Proc Natl Acad Sci USA 110, E716-725. Tarchini B, Jolicoeur C, Cayouette M. 2012. In vivo evidence for unbiased Ikaros retinal lineages using an Ikaros-Cre mouse line driving clonal recombination. Developmental Dynamics 241, 1973-1985. Tschopp P, Tarchini B, Spitz, F, Zakany J, Duboule D. 2009. Uncoupling time and space in the collinear regulation of Hox genes. PLoS Genetics 5, e1000398. Tarchini B, Duboule D, Kmita M. 2006. Regulatory constraints in the evolution of the tetrapod limb anterior-posterior polarity. Nature 443, 985- 988. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology 29 www.jax.org/research

Jennifer Trowbridge, Ph.D. Assistant Professor Hematopoietic stem cells (HSCs) serve as the backbone of the hematopoietic system, undergoing self-renewal and differentiation to generate the cells of all of the blood lineages. In several types of blood cancers, leukemia stem cells (LSCs) with analogous properties that underlie the expansion of malignant cells have been defined. The Trowbridge lab focuses on the epigenetic regulation of gene expression in these cell types, including DNA methylation and modifications of the histone code. We seek to answer two central questions pertaining to the epigenetic regulation self-renewal. One, are the epigenetic mechanisms responsible for regulating gene expression and self-renewal similar or distinct in HSCs versus LSCs? Two, are epigenetic patterns within HSCs or LSCs programmed in response to cues from the bone marrow microenvironment? By identifying key differences in the epigenetic mechanisms underlying the regulation of HSCs and LSCs, we seek to reveal novel targets for therapy of leukemia.

Trowbridge JJ, Sinha AU, Zhu N, Li M, Armstrong SA, Orkin AH. 2012. Haploinsufficiency of Dnmt1 impairs leukemia stem cell function through derepression of bivalent chromatin domains. Genes and Development 26(4): 344-349. Trowbridge JJ, Orkin SH. 2011. Dnmt3a silences hematopoietic stem cell self- renewal. Nature Genetics 44(1): 13-14. Trowbridge JJ, Orkin SH. 2010. DNA methylation in adult stem cells: New insights into self-renewal. Epigenetics 5(3). Trowbridge JJ, Snow JW, Kim J, Orkin SH. 2009. DNA methltransferase 1 is essential for and uniquely regulates hematopoietic stem and progenitor cells. Cell Stem Cell 5(4): 442-449. Trowbridge JJ, Xenocostas A, Moon RT, Bhatia M. 2006.Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nature Medicine 12(1): 89-98 Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology www.jax.org/research 30

Zhong-wei Zhang, Ph.D. Associate Professor Our laboratory studies the development and function of neural circuits in the brain with goals to elucidate mechanisms of developmental brain disorder. We use a variety of experimental approaches, including electrophysiology, molecular genetics, anatomy, and behavior analysis. Three major research focuses are 1) cellular and molecular mechanisms underlying pruning and strengthening of excitatory synapses during early life, 2) functional organization of inhibitory circuits in the thalamus, and 3) dysfunction of neural circuits in genetic models of autism spectrum disorders.

Zhang ZW, Peterson M, Liu H. (2013) Essential role of postsynaptic NMDA receptors in developmental refinement of excitatory synapses. Proc Natl Acad Sci USA. In press. Wang H, Liu H, Zhang ZW. (2011) Elimination of redundant synaptic inputs in the absence of synaptic strengthening. J. Neurosci. 31:16675-84 Wang H, Liu H, Storm D, Zhang ZW (2011) Adenylate cyclase 1 promotes strengthening and experience-dependent plasticity of whisker relay synapses in the thalamus. J Physiol (London)589:5649-62. Zhang ZW, Zak JD, Liu H. (2010) MeCP2 is required for normal development of GABAergic circuits in the thalamus. J Neurophysiol 103(5):2470-2481. Wang H, Zhang ZW. (2008) A critical window for experience-dependent plasticity at whisker sensory relay synapse in the thalamus. J Neurosci 28(50):13621-13628. Arsenault D, Zhang ZW. (2006) Developmental remodeling of the lemniscal synapse in the ventral basal thalamus of the mouse. J Physiol (London) 573:121- 132. Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics • Genomics • Development Biology • Cardiovascular Biology • Computational Aging • Bioinformatics Cells • Stem Tools • Research • Neurobiology • Metabolism • Immunology/Inflammation Hematology 31 www.jax.org/research our JAX’s collaborative programs. collaborative JAX’s our about more learn http://sackler.tufts.edu or http://www.biomedsci.umaine.edu to visit http://education.jax.org/predoc/index.html, Please ofMaine. University Engineering, and Sciences ofBiological School and Graduate University Tufts School, Sackler with programs Ph.D. collaborative has JAX institutions. academic individual atthe handled are programs Ph.D. to academic Applications your anddiscuss interests opportunities. possible to member afaculty contact also may you atJAX, studying in interested are you If [email protected] Tel: 207-288-6000 Harbor, Bar 04609 ME St., Main 600 Laboratory Jackson The Education and Training Education and Training ([email protected]). of Office the contact please atJAX, research graduate conducting about information more For experience. research previous with those especially records, academic strong with students We seek Inquiries

Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics Hematology • Immunology/Inflammation • Metabolism • Neurobiology • Research Tools • Stem Cells global biomedicalglobal community inour shared quest to improve human health. The Laboratory’s mission is to discover precise genomic solutions for and empower disease the for genomic medicine inFarmington, Conn. Headquartered inBar Harbor, Maine, it has a facility inSacramento, and Calif., institute anew National Cancer Institute-designated Cancer Center with more than 1,400employees. The Jackson Laboratory is an independent, nonprofit biomedical research institution and About TheJackson Laboratory degeneration,macular neurodegenerative diseases Neurobiology: Blindness, cerebellar disorders, deafness, epilepsy, glaucoma, Metabolic diseases:Atherosclerosis, diabetes, gallstones, hypertension, obesity tissue transplant rejection Immunology: HIV-AIDS, autoimmunity, immune system disorders, lupus, determination,sex aging, osteoporosis Developmental andreproductive biology: Down defects, syndrome, Birth comparative genomics Computational biology andbioinformatics: Mouse genome informatics, ovarian; initiation and progression; detection and therapies Cancer: Brain, breast, leukemia, lung, lymphoma, and conditions through sixmajor research programs: scientistsOur are working to understand and solve variety of awide diseases Our research programs Aging • Bioinformatics • Computational Biology • Cardiovascular Biology • Development • Genomics Hematology • Immunology/Inflammation • Metabolism • Neurobiology • Research Tools • Stem Cells 600 Main Street, Bar Harbor, 04609-1523 ME Bar Street, Main 600