Overview
Our research focuses on hematopoiesis in the mouse. We use both genotype- and phenotype-driven approaches to study red blood cell structure, function and survival. Our current projects focus on three major themes. First is the identification of embryonic globin expression, critical to sickle cell disease therapy. Second is analysis of aberrant Ras signaling and function, which leads to hematopoietic failure in a mutant mouse model. Third is investigating the role of genetic variation among inbred mouse strains to determine baseline blood values, known risk factors all-cause mortality as well as sickle cell disease, stroke and cardiovascular disease.
Scientific report
Genetics of Blood Cell Development and Disease
Since my pre- and post-doctoral training in the laboratories of Drs. Jane E. Barker (The Jackson Laboratory) and Samuel E. Lux (Children's Hospital, Harvard Medical School), I have devoted my research efforts to studying hematopoiesis in the mouse, investigating both single gene (Mendelian) defects and complex, polygenic phenotypes that arise from natural genetic variation in inbred strains and other reference mouse populations. We utilize the most state-of-the-art genetic techniques in both genotype- and phenotype-driven approaches to identify and functionally analyze genes critical to erythropoiesis and red cell structure, function, and survival including gene targeting, positioning cloning, and mutagenesis.
We have over the years produced more than a dozen knockouts, including conditional knockouts, and positionally cloned nine spontaneous and chemically induced mouse mutants. In all cases, we went on to extensively phenotype the mutant animals and identify mechanisms leading to the abnormal phenotypes. Our complex traits (QTL) analyses to date have focused primarily on understanding 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, stroke, cardiovascular disease, and all-cause mortality. We utilize extensive, high-throughput phenotyping; state-of-the-art genetics, including analysis of inbred and recombinant inbred strains, congenic strains, F2 and 4-way crosses, and other reference mouse populations, such as the Collaborative Cross RI (recombinant inbred) lines and DO (diversity outbred mice); statistical analyses (R/qtl, QTL/REL, combined cross analysis); bioinformatics methods (interval-specific haplotype analysis, comparative genomics), and genome wide association methods to identify loci influencing traits of interest and to narrow confidence intervals to obtain as small a list of candidate genes as possible for functional analyses.
Current projects focus on three major themes. First is the identification of loci influencing embryonic globin expression, critical to sickle cell disease therapy, using unbiased QTL approaches. These include analyses of Diversity Outbred mice as well as backcross progeny derived from mouse mutant strains over-expressing embryonic globins in adult erythroid tissues. A second major project focuses on analysis of aberrant Ras signaling and function in the scat mutant mouse model, which carries a mutation in a Ras GTPase activating protein. As scat mutants succumb to hematopoietic failure at ~30 days of age, we are using knockin and lineage-specific targeting approaches to assess whether Ras-mediated oncogenesis occurs as scat mice age. The third major project is complex traits analyses to understand the role of natural genetic variation among inbred strains of mice in determining baseline peripheral blood values, known risk factors for sickle cell disease, stroke, cardiovascular disease, and all-cause mortality.
Lab staff
Principal Investigator: Luanne L. Peters, Ph.D.
Research Scientist: Raymond Robledo, Ph.D.
Postdoctoral Associates: Yue Zhao, Ph.D., Danitza Nebor, Ph.D.
Research Administrative Assistant: Maxine Friend
Publication listings
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.
Robledo RF, Seburn KL, Nicholson A, Burgess RW, Peters LL. 2012. Strain-specific hyperkyphosis and megaesophagus in Add1 null mice. Genesis, in press.
Paigen B, Svenson KL, Smith RV, Marion MA, Stearns T, Peters LL, Smith AL. 2012. Physiological effects of housing density on C57BL/6J mice over a 9-month period. J Anim Sci, in press.
Kodippili GC, Spector J, Hale J, Giger K, Hughes MR, McNagny KM, Birkenmeier C, Peters LL, Ritchie K, Low PS. 2012. Analysis of the mobilities of band 3 populations associated with ankyrin protein and junctional complexes in intact murine erythrocytes. J Biol Chem 287, 4129-4138.
Yang S, Weng H, Chen L, Guo X, Parra M, Conboy J, Debnath G, Lambert AJ, Peters LL, Baines AJ, Mohandas N, An X. 2011. Lack of protein 4.1G causes altered expression and localization of the cell adhesion molecule nectin-like 4 in testis and can cause male infertility. Mol Cell Biol. 31, 2276-2286.
Amigo JD, Yu M, Troadec MB, Gwynn B, Cooney JD, Lambert AJ, Chi NC, Weiss MJ, Peters LL, Kaplan J, Cantor AB, Paw BH. 2011. Identification of distal cis-regulatory elements at mouse mitoferrin loci using zebrafish transgenesis. Mol Cell Biol. 31, 1344-1356.
Hughes MR, Anderson N, Maltby S, Wong J, Berberovic Z, Birkenmeier CS, Haddon DJ, Garcha K, Flenniken A, Osborne LR, Adamson SL, Rossant J, Peters LL, Minden MD, Paulson RF, Wang C, Barber DL, McNagny KM, Stanford WL. 2011. A novel ENU-generated truncation mutation lacking the spectrin-binding and C-terminal regulatory domains of Ank1 models severe hemolytic hereditary spherocytosis. Exp Hemotol. 39, 305-320.
Berndt A, Leme AS, Williams LK, Von Smith R, Savage HS, Stearns TM, Tsaih SW, Shapiro SD, Peters LL, Paigen B, Svenson KL. 2011. Comparison of unrestrained plethysmography and forced oscillation for identifying genetic variability of airway responsiveness in inbred mice. Physiol Genomics. 43, 1-11.
Peters LL, Shavit JA, Lambert AJ, Tsaih SW, Li Q, Su Z, Leduc MS, Paigen B, Churchill GA, Ginsburg D, Brugnara C. 2010. Sequence variation at multiple loci influences red cell hemoglobin concentration. 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.
Moyer JD, Nowak RB, Kim NE, Larkin SK, Peters LL, Hartwig J, Kuypers FA, Fowler VM. 2010. Tropomodulin 1-null mice have a mild spherocytic elliptocytosis with appearance of tropomodulin 3 in red blood cells and disruption of the membrane skeleton. Blood. 116, 2590-2599.
Stankewich MC, Gwynn B, Ardito T, Ji L, Kim J, Robledo RF, Lux SE, Peters LL, Morrow JS. 2010. Targeted deletion of betaIII spectrin impairs synaptogenesis and generates ataxic and seizure phenotypes. Proc Natl Acad Sci USA 107, 6022-6027.
Robledo RF, Lambert AJ, Birkenmeier CS, Cirlan MV, 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 in {alpha}-spectrin deficient red cells. Blood 115, 1804-1814.
Korsgen C. Peters LL, Lux SE. 2010. Protein 4.2 binds to the carboxyterminal EF-hands of erythroid alpha spectrin in a calcium and calmodulin dependent manner. J Biol Chem 285, 4757-4770.
Ferrandi M, Cusi D, Molinari I, Del Vecchio L, Barlassina C, Rastaldi MP, Schena FP, Macciardi F, Marcantoni C, Roccatello D, Peters LL, Armelloni S, Min L, Giardino L, Mattinzoli D, Camisasca C, Palazzo F, Manunta P, Ferrari P, Bianchi G. 2010. alpha- and beta-Adducin polymorphisms affect podocyte proteins and proteinuria in rodents and decline of renal function in human IgA nephropathy. J Mol Med 88, 203-217.
Sahr KE, Lambert AJ, Ciciotte SL, Peters LL. 2009. Targeted deletion of the g-adducin gene (Add3) in mice reveals differences in a-adducin interactions in erythroid and nonerythroid cells. Am J Hematol 84, 354-361.
Yuan R, Tsaih SW, Petkova S, Evsikova CM, Xing S, Marion M, Bogue M, Mills K, Peters LL, Bult C, Rosen CJ, Sundberg JP, Harrison DE, Churchill GA, Paiden BJ. 2009. Aging in 31 inbred strains of mice: study design and interim report on median lifespans. Aging Cell 8, 277-287.
Svenson KL, Ahituv N, Durgin RS, Savage H, Magnani PA, Foreman O, Paigen B, Peters LL. 2008. A new mouse mutant for the LDL receptor identified using ENU mutagenesis. J Lipid Res 49, 2452-2462.
Campanella ME, Chishti A, Wandersee NJ, Peters LL, Narla M, Gilligan D, Low PS. 2008. Characterization of glycolytic enzyme interactions with murine erythrocyte membranes in wild type and membrane protein knockout mice. Blood 112, 3900-3906.
Robledo RF, Ciciotte SL, Gwynn B, Sahr KE, Gilligan DM, Peters LL. 2008. Targeted deletion of a -adducin results in absent b - and g -adducin, compensated hemolytic anemia, and hydrocephalus in mice. Blood 112, 4298-4307.
Alper SL, Vandorpe DH, Peters LL, Brugnara C. 2008. Reduced DIDS-sensitive chloride conductance in Ae1-/- mouse erythrocytes. Blood Cells Mol Dis 41, 22-34.
Li R, Svenson KL, Peters LL, Churchill GA. 2008. The relationships of dietary fat, body composition and bone mineral density in inbred mouse strain panels. Physiol Gen 33, 26-32.
Svenson KL, Smith RV, Magnani PA, Suetin HR, Paigen B, Naggert JA, Churchill GA, Peters LL. 2007. Multiple trait measurements in 43 inbred mouse strains captures the phenotypic diversity characteristic of human populations. J App Physiol 102, 2369-78.
Peters LL. 2007. Spectrin unfolding mutations: kinks in the links. Blood 109:3133-3134.
Peters LL, Robledo RF, Bult CJ, Churchill GA, Paigen BJ, Svenson KL. 2007. The mouse as a model for understanding human biology: a resource guide for complex trait analysis. Nat Gen Rev 8, 58-69.
Stehberger P, Shmukler BE, Stuart-Tilley AK, Peters LL, Alper SL, Wagner CA. 2007. Distal renal tubular acidosis in mice lacking the AE1 (band 3) Cl-/HCO3 exchanger (Slc4a1). J Am Soc Nephrol 18:1408-1418.
Chen H, Khan AA, Liu F, Gilligan DM, Peters LL, Messick J, Haschek-Hock WM, Li X, Ostafin AE, Chishti AH. 2007. Combined deletion of mouse dematin-headpiece and beta-adducin exerts a novel effect on the spectrin-actin junctions leading to erythrocyte fragility and hemolytic anemia. J Biol Chem, 282:4124-35.
Pack AI, Galante RJ, Cater J, Maislin G, Metaxas D, Lu S, Zhang L, Smith RV, Kay T, Lian, J, Svenson KL, Peters LL. 2007. A novel method for high throughput phenotyping of sleep and wakefulness in mice with application to mutagenesis. Physiol Gen 28:232-238.
Soni S, Shashi B, Gwynn B, Sahr KE, Peters LL, Hanspal M. 2006. EMP null mice are non-viable and exhibit erythroid and macrophage differentiation defects. J Biol Chem 281:20181-20190.
Rivera A, De Franceschi L, Bize I, Peters LL, Gascard P, Mohandas N, Brugnara C. 2006. Effect of complete protein 4.1R deficiency on ion transport properties of murine erythrocytes. Am J Physiol 291, C880-C886.
Gwynn B, Smith RS, Rowe LB, Taylor BA, Peters LL. 2006. A mouse TRAPP related protein is involved in pigmentation. Genomics 88, 196-203.
Peters LL, Lambert AJ, Zhang W, Churchill GA, Brugnara C, Platt OS. 2006. Quantitative trait loci for baseline erythroid traits. Mamm Genome 17, 298-309.
Inoue Y, Peters LL, Yim SH, Inoue J, Gonzalez FJ. 2006. Hepatocyte nuclear factor 4a is critical for blood coagulation homeostasis. J Mol Med 84, 334-344.
Shaw GC, Cope JJ, Li L, Corson K, Hersey C, Ackermann GE, Wingert RE, Trede NS, Traver D, Barut BA, Gwynn B, Minet E, Donovan A, Brownlie A, Weiss ME, Peters LL, Zon LI, Kaplan J, Paw BH. 2006. Frascati, a mitochondrial transporter of iron for heme biosynthesis, is essential in developing erythroblasts. Nature 440, 96-100.