ZFIN ID: ZDB-LAB-090707-2
North Lab
PI/Director: North, Trista
Contact Person: North, Trista
Email: trista.north@childrens.harvard.edu
Address: Harvard Medical School Stem Cell Program Department of Hematology/Oncology Boston Children’s Hospital 300 Longwood Avenue, RB 05214 Boston MA 02115
Country: United States
Phone: 617-919-6410
Line Designation: None assigned


Regenerative medicine holds great promise to alleviate morbidity and mortality
in patients suffering from organ failure. Pathways that govern stem cell
behavior and organ development can be modulated to affect adult organ repair and
regeneration. Our laboratory focuses on developmental hematopoiesis as a key to
uncovering general principles of stem cell function, self-renewal and tissue
regeneration. Hematopoietic stem cells (HSCs) give rise to each of the blood
lineages found in the adult vertebrate; the gene programs regulating HSC
development and homeostasis are highly evolutionarily conserved. We are using
the zebrafish as a model system to discover novel regulators of HSC formation.
In addition, we employ murine models to document evolutionary conservation of
these signaling pathways during development and in hematopoietic regeneration
following injury or transplantation.

Through a chemical genetic screening approach, we identified several novel
compound modifiers of blood stem cell formation; each pathway isolated in the
screen altered the normal expression pattern of the conserved HSC marker runx1.
This methodology led to the first example of FDA approval for the
investigational use of a compound identified in an unbiased screen in zebrafish
for clinical application in the treatment of human disease. Our laboratory will
use both chemical and genetic approaches in the zebrafish to characterize novel
mechanisms controlling HSC induction in the vertebrate embryo. Additionally,
through comparative genomic examination of zebrafish and murine sites of
embryonic hematopoiesis, we aim to decipher regulatory networks that are central
to HSC formation and function. Using chemical ablation, irradiation injury and
transplantation approaches, we will further define the functional conservation
of HSC regulators identified in the embryonic screens in controlling adult
marrow homeostasis in zebrafish and mice. Xenotransplantation experiments using
human cord blood with be employed to investigate translational potential. The
work in our laboratory has direct relevance for the development of novel
therapeutic strategies for controlling leukemogenesis and enhancing stem cell
transplantation biology.

Dovey, Michael Post-Doc Polok, Bozena Post-Doc Harris, James Fish Facility Staff
Vedder, Lea Fish Facility Staff

Frame, J.M., Kubaczka, C., Long, T.L., Esain, V., Soto, R.A., Hachimi, M., Jing, R., Shwartz, A., Goessling, W., Daley, G.Q., North, T.E. (2020) Metabolic Regulation of Inflammasome Activity Controls Embryonic Hematopoietic Stem and Progenitor Cell Production. Developmental Cell. 55(2):133-149.e6
Harris, J.M., Wang, A.Y., Boulanger-Weill, J., Santoriello, C., Foianini, S., Lichtman, J.W., Zon, L.I., Arlotta, P. (2020) Long-Range Optogenetic Control of Axon Guidance Overcomes Developmental Boundaries and Defects. Developmental Cell. 53:577-588.e7
Chaturantabut, S., Shwartz, A., Garnaas, M.K., LaBella, K., Li, C.C., Carroll, K.J., Cutting, C.C., Budrow, N., Palaria, A., Gorelick, D.A., Tremblay, K.D., North, T.E., Goessling, W. (2020) Estrogen acts via estrogen receptor 2b to regulate hepatobiliary fate during vertebrate development. Hepatology (Baltimore, Md.). 72(5):1786-1799
Lundin, V., Sugden, W.W., Theodore, L.N., Sousa, P.M., Han, A., Chou, S., Wrighton, P.J., Cox, A.G., Ingber, D.E., Goessling, W., Daley, G.Q., North, T.E. (2020) YAP Regulates Hematopoietic Stem Cell Formation in Response to the Biomechanical Forces of Blood Flow. Developmental Cell. 52(4):446-460.e5
Kinney, M.A., Vo, L.T., Frame, J.M., Barragan, J., Conway, A.J., Li, S., Wong, K.K., Collins, J.J., Cahan, P., North, T.E., Lauffenburger, D.A., Daley, G.Q. (2019) A systems biology pipeline identifies regulatory networks for stem cell engineering. Nature Biotechnology. 37:810-818
Chaturantabut, S., Shwartz, A., Evason, K.J., Cox, A.G., Labella, K., Schepers, A.G., Yang, S., Aravena, M., Houvras, Y., Mancio-Silva, L., Romano, S., Gorelick, D.A., Cohen, D.E., Zon, L.I., Bhatia, S.N., North, T.E., Goessling, W. (2019) Estrogen Activation of G protein-coupled Estrogen Receptor 1 Regulates Phosphoinositide 3-kinase and mTOR Signaling to Promote Liver Growth in Zebrafish and Proliferation of Human Hepatocytes. Gastroenterology. 156(6):1788-1804.e13
Oo, Z.M., Illendula, A., Grembecka, J., Schmidt, C., Zhou, Y., Esain, V., Kwan, W., Frost, I., North, T.E., Rajewski, R.A., Speck, N.A., Bushweller, J.H. (2017) A tool compound targeting the core binding factor Runt domain to disrupt binding to CBFβ in leukemic cells. Leukemia & lymphoma. 59(9):2188-2200
Theodore, L.N., Hagedorn, E.J., Cortes, M., Natsuhara, K., Liu, S.Y., Perlin, J.R., Yang, S., Daily, M.L., Zon, L.I., North, T.E. (2017) Distinct Roles for Matrix Metalloproteinases 2 and 9 in Embryonic Hematopoietic Stem Cell Emergence, Migration, and Niche Colonization. Stem Cell Reports. 8(5):1226-1241
Lim, S.E., Esain, V., Kwan, W., Theodore, L.N., Cortes, M., Frost, I.M., Liu, S.Y., North, T.E. (2017) HIF1α-induced PDGFRβ signaling promotes developmental HSC production via IL-6 activation. Experimental hematology. 46:83-95.e6
Frame, J.M., Lim, S.E., North, T.E. (2017) Hematopoietic stem cell development: Using the zebrafish to identify extrinsic and intrinsic mechanisms regulating hematopoiesis. Methods in cell biology. 138:165-192
Kwan, W., North, T.E. (2017) Netting Novel Regulators of Hematopoiesis and Hematologic Malignancies in Zebrafish. Current topics in developmental biology. 124:125-160
North, T.E., Goessling, W. (2016) Haematopoietic stem cells show their true colours. Nature cell biology. 19:10-12
Konantz, M., Alghisi, E., Müller, J.S., Lenard, A., Esain, V., Carroll, K.J., Kanz, L., North, T.E., Lengerke, C. (2016) Evi1 regulates Notch activation to induce zebrafish hematopoietic stem cell emergence. The EMBO journal. 35(21):2315-2331
Cortes, M., Chen, M.J., Stachura, D.L., Liu, S.Y., Kwan, W., Wright, F., Vo, L.T., Theodore, L.N., Esain, V., Frost, I.M., Schlaeger, T.M., Goessling, W., Daley, G.Q., North, T.E. (2016) Developmental Vitamin D Availability Impacts Hematopoietic Stem Cell Production. Cell Reports. 17:458-468
Nissim, S., Weeksb, O., Talbot, J.C., Hedgepeth, J.W., Wucherpfennig, J., Schatzman-Bone, S., Swinburne, I., Cortes, M., Alexa, K., Megason, S., North, T.E., Amacher, S.L., Goessling, W. (2016) Iterative use of nuclear receptor Nr5a2 regulates multiple stages of liver and pancreas development. Developmental Biology. 418(1):108-23
Kwan, W., Cortes, M., Frost, I., Esain, V., Theodore, L.N., Liu, S.Y., Budrow, N., Goessling, W., North, T.E. (2016) The Central Nervous System Regulates Embryonic HSPC Production via Stress-Responsive Glucocorticoid Receptor Signaling. Cell Stem Cell. 19:370-82
Moore, F.E., Garcia, E.G., Lobbardi, R., Jain, E., Tang, Q., Moore, J.C., Cortes, M., Molodtsov, A., Kasheta, M., Luo, C.C., Garcia, A.J., Mylvaganam, R., Yoder, J.A., Blackburn, J.S., Sadreyev, R.I., Ceol, C.J., North, T.E., Langenau, D.M. (2016) Single-cell transcriptional analysis of normal, aberrant, and malignant hematopoiesis in zebrafish. The Journal of experimental medicine. 213(6):979-92
Kanz, D., Konantz, M., Alghisi, E., North, T.E., Lengerke, C. (2016) Endothelial-to-hematopoietic transition: Notch-ing vessels into blood. Annals of the New York Academy of Sciences. 1370(1):97-108
Liu, L.Y., Alexa, K., Cortes, M., Schatzman-Bone, S., Kim, A.J., Mukhopadhyay, B., Cinar, R., Kunos, G., North, T.E., Goessling, W. (2016) Cannabinoid receptor signaling regulates liver development and metabolism. Development (Cambridge, England). 143:609-22
Esain, V., Cortes, M., North, T.E. (2016) Enumerating Hematopoietic Stem and Progenitor Cells in Zebrafish Embryos. Methods in molecular biology (Clifton, N.J.). 1451:191-206
Cortes, M., Liu, S.Y., Kwan, W., Alexa, K., Goessling, W., North, T.E. (2015) Accumulation of the Vitamin D Precursor Cholecalciferol Antagonizes Hedgehog Signaling to Impair Hemogenic Endothelium Formation. Stem Cell Reports. 5:471-9
Esain, V., Kwan, W., Carroll, K.J., Cortes, M., Liu, S.Y., Frechette, G.M., Sheward, L.M., Nissim, S., Goessling, W., North, T.E. (2015) Cannabinoid Receptor-2 Regulates Embryonic Hematopoietic Stem Cell Development via PGE2 and P-selectin Activity. Stem cells (Dayton, Ohio). 33(8):2596-612
Li, Y., Esain, V., Teng, L., Xu, J., Kwan, W., Frost, I.M., Yzaguirre, A.D., Cai, X., Cortes, M., Maijenburg, M.W., Tober, J., Dzierzak, E., Orkin, S.H., Tan, K., North, T.E., Speck, N.A. (2014) Inflammatory signaling regulates embryonic hematopoietic stem and progenitor cell production. Genes & Development. 28(23):2597-612
Carroll, K.J., North, T.E. (2014) Oceans of Opportunity: Exploring Vertebrate Hematopoiesis in Zebrafish. Experimental hematology. 42(8):684-696
Goessling, W., North, T.E. (2014) Repairing quite swimmingly: advances in regenerative medicine using zebrafish. Disease models & mechanisms. 7:769-776
Carroll, K.J., Esain, V., Garnaas, M.K., Cortes, M., Dovey, M.C., Nissim, S., Frechette, G.M., Liu, S.Y., Kwan, W., Cutting, C.C., Harris, J.M., Gorelick, D.A., Halpern, M.E., Lawson, N.D., Goessling, W., North, T.E. (2014) Estrogen defines the dorsal-ventral limit of VEGF regulation to specify the location of the hemogenic endothelial niche. Developmental Cell. 29:437-53
Kotkamp, K., Kur, E., Wendik, B., Polok, B.K., Ben-Dor, S., Onichtchouk, D., Driever, W. (2014) Pou5f1/Oct4 promotes cell survival via direct activation of mych expression during zebrafish gastrulation. PLoS One. 9:e92356
Nissim, S., Sherwood, R.I., Wucherpfennig, J., Saunders, D., Harris, J.M., Esain, V., Carroll, K.J., Frechette, G.M., Kim, A.J., Hwang, K.L., Cutting, C.C., Elledge, S., North, T.E., and Goessling, W. (2014) Prostaglandin E2 regulates liver versus pancreas cell-fate decisions and endodermal outgrowth. Developmental Cell. 28(4):423-437
Cox, A.G., Saunders, D.C., Kelsey, P.B., Conway, A.A., Tesmenitsky, Y., Marchini, J.F., Brown, K.K., Stamler, J.S., Colagiovanni, D.B., Rosenthal, G.J., Croce, K.J., North, T.E., and Goessling, W. (2014) S-Nitrosothiol Signaling Regulates Liver Development and Improves Outcome following Toxic Liver Injury. Cell Reports. 6(1):56-69
Liu, L.Y., Fox, C.S., North, T.E., and Goessling, W. (2013) Functional validation of GWAS gene candidates for abnormal liver function during zebrafish liver development. Disease models & mechanisms. 6(5):1271-8
Harris, J.M., Esain, V., Frechette, G.M., Harris, L.J., Cox, A.G., Cortes, M., Garnaas, M.K., Carroll, K.J., Cutting, C.C., Khan, T., Elks, P.M., Renshaw, S.A., Dickinson, B.C., Chang, C.J., Murphy, M.P., Paw, B.H., Vander Heiden, M.G., Goessling, W., and North, T.E. (2013) Glucose metabolism impacts the spatio-temporal onset and magnitude of HSC induction in vivo. Blood. 121(13):2483-2493
Page, L., Polok, B., Bustamante, M., and Schorderet, D.F. (2013) Bigh3 Is Upregulated in Regenerating Zebrafish Fin. Zebrafish. 10(1):36-42
Cooney, J.D., Hildick-Smith, G.J., Shafizadeh, E., McBride, P.F., Carroll, K.J., Anderson, H., Shaw, G.C., Tamplin, O.J., Branco, D.S., Dalton, A.J., Shah, D.I., Wong, C., Gallagher, P.G., Zon, L.I., North, T.E., and Paw, B.H. (2013) Teleost growth factor independence (gfi) genes differentially regulate successive waves of hematopoiesis. Developmental Biology. 373(2):431-441
Yen, J., White, R.M., Wedge, D.C., Van Loo, P., de Ridder, J., Capper, A., Richardson, J., Jones, D., Raine, K., Watson, I.R., Wu, C.J., Cheng, J., Martincorena, I., Nik-Zainal, S., Mudie, L., Moreau, Y., Marshall, J., Ramakrishna, M., Tarpey, P., Shlien, A., Whitmore, I., Gamble, S., Latimer, C., Langdon, E., Kaufman, C., Dovey, M., Taylor, A., Menzies, A., McLaren, S., O Meara, S., Butler, A., Teague, J., Lister, J., Chin, L., Campbell, P., Adams, D.J., Zon, L.I., Patton, E.E., Stemple, D.L., and Futreal, P.A. (2013) The genetic heterogeneity and mutational burden of engineered melanomas in zebrafish models. Genome biology. 14(10):R113
Garnaas, M.K., Cutting, C.C., Meyers, A., Kelsey, P.B., Harris, J.M., North, T.E., and Goessling, W. (2012) Rargb regulates organ laterality in a zebrafish model of right atrial isomerism. Developmental Biology. 372(2):178-189
Leshchiner, I., Alexa, K., Kelsey, P., Adzhubei, I., Austin, C., Cooney, J., Anderson, H., King, M., Stottman, R., Ha, S., Drummond, I., Paw, B.H., North, T., Beier, D., Goessling, W., and Sunyaev, S. (2012) Mutation mapping and identification by whole genome sequencing. Genome research. 22(8):1541-1548
Shaik, S., Nucera, C., Inuzuka, H., Gao, D., Garnaas, M., Frechette, G., Harris, L., Wan, L., Fukushima, H., Husain, A., Nose, V., Fadda, G., Sadow, P.M., Goessling, W., North, T., Lawler, J., and Wei, W. (2012) SCFβ-TRCP suppresses angiogenesis and thyroid cancer cell migration by promoting ubiquitination and destruction of VEGF receptor 2. The Journal of experimental medicine. 209(7):1289-1307
Colanesi, S., Taylor, K.L., Temperley, N.D., Lundegaard, P.R., Liu, D., North, T.E., Ishizaki, H., Kelsh, R.N., and Patton, E.E. (2012) Small molecule screening identifies targetable zebrafish pigmentation pathways. Pigment cell & melanoma research. 25(2):131-143
Saadi, I., Alkuraya, F.S., Gisselbrecht, S.S., Goessling, W., Cavallesco, R., Turbe-Doan, A., Petrin, A.L., Harris, J., Siddiqui, U., Grix, A.W., Hove, H.D., Leboulch, P., Glover, T.W., Morton, C.C., Richieri-Costa, A., Murray, J.C., Erickson, R.P., and Maas, R.L. (2011) Deficiency of the Cytoskeletal Protein SPECC1L Leads to Oblique Facial Clefting. American journal of human genetics. 89(1):44-55
Gibert, Y., Lattanzi, V.J., Zhen, A.W., Vedder, L., Brunet, F., Faasse, S.A., Babitt, J.L., Lin, H.Y., Hammerschmidt, M., and Fraenkel, P.G. (2011) BMP Signaling Modulates Hepcidin Expression in Zebrafish Embryos Independent of Hemojuvelin. PLoS One. 6(1):e14553
Goessling, W., and North, T.E. (2011) Hematopoietic stem cell development: using the zebrafish to identify the signaling networks and physical forces regulating hematopoiesis. Methods in cell biology. 105:117-136
North, T.E., Babu, I.R., Vedder, L.M., Lord, A.M., Wishnok, J.S., Tannenbaum, S.R., Zon, L.I., and Goessling, W. (2010) PGE2-regulated wnt signaling and N-acetylcysteine are synergistically hepatoprotective in zebrafish acetaminophen injury. Proceedings of the National Academy of Sciences of the United States of America. 107(40):17315-17320
Brennan, C., Dosch, R., Haramis, A.P., Luckenbacher, T., Martinez-Morales, J.R., Moro, E., Polok, B., Ramesh, T.M., Russell, C., Argenton, F., and Strähle, U. (2010) Report of the European Zebrafish Principal Investigator Meeting in Padua, Italy, March 18-22, 2010. Zebrafish. 7(3):305-310
Onichtchouk, D., Geier, F., Polok, B., Messerschmidt, D., Mössner, R., Wendik, B., Song, S., Taylor, V., Timmer, J., and Driever, W. (2010) Zebrafish Pou5f1-dependent transcriptional networks in temporal control of early development. Molecular Systems Biology. 6:354
Dovey, M., White, R.M., and Zon, L.I. (2009) Oncogenic NRAS Cooperates with p53 Loss to Generate Melanoma in Zebrafish. Zebrafish. 6(4):397-404
Dovey, M., Patton, E.E., Bowman, T., North, T., Goessling, W., Zhou, Y., and Zon, L.I. (2009) Topoisomerase II alpha is required for embryonic development and liver regeneration in zebrafish. Molecular and cellular biology. 29(13):3746-3753
North, T.E., Goessling, W., Peeters, M., Li, P., Ceol, C., Lord, A.M., Weber, G.J., Harris, J., Cutting, C.C., Huang, P., Dzierzak, E., and Zon, L.I. (2009) Hematopoietic stem cell development is dependent on blood flow. Cell. 137(4):736-748
Goessling, W., North, T.E., Loewer, S., Lord, A.M., Lee, S., Stoick-Cooper, C.L., Weidinger, G., Puder, M., Daley, G.Q., Moon, R.T., and Zon, L.I. (2009) Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration. Cell. 136(6):1136-1147
Polok, B., Escher, P., Ambresin, A., Chouery, E., Bolay, S., Meunier, I., Nan, F., Hamel, C., Munier, F.L., Thilo, B., Mégarbané, A., and Schorderet, D.F. (2009) Mutations in CNNM4 cause recessive cone-rod dystrophy with amelogenesis imperfecta. American journal of human genetics. 84(2):259-265
Dovey, M.C. (2009) Genetic analysis of vertebrate cell cycles and melanoma in zebrafish. Ph.D. Thesis. :164p
Dovey, M.C., and Zon, L.I. (2009) Defining cancer stem cells by xenotransplantation in zebrafish. Methods in molecular biology (Clifton, N.J.). 568:1-5
Upadhyay, G., Goessling, W., North, T.E., Xavier, R., Zon, L.I., and Yajnik, V. (2008) Molecular association between beta-catenin degradation complex and Rac guanine exchange factor DOCK4 is essential for Wnt/beta-catenin signaling. Oncogene. 27(44):5845-5855
Goessling, W., North, T.E., Lord, A.M., Ceol, C., Lee, S., Weidinger, G., Bourque, C., Strijbosch, R., Haramis, A.P., Puder, M., Clevers, H., Moon, R.T., and Zon, L.I. (2008) APC mutant zebrafish uncover a changing temporal requirement for wnt signaling in liver development. Developmental Biology. 320(1):161-174
Boisset, G., Polok, B.K., and Schorderet, D.F. (2008) Characterization of pip5k3 fleck corneal dystrophy-linked gene in zebrafish. Gene expression patterns : GEP. 8(6):404-410
Schorderet, D.F., Nichini, O., Boisset, G., Polok, B., Tiab, L., Mayeur, H., Raji, B., de la Houssaye, G., Abitbol, M.M., and Munier, F.L. (2008) Mutation in the Human Homeobox Gene NKX5-3 Causes an Oculo-Auricular Syndrome. American journal of human genetics. 82(5):1178-1184
White, R.M., Sessa, A., Burke, C., Bowman, T., LeBlanc, J., Ceol, C. Bourque, C., Dovey, M., Goessling, W., Burns, C.E., and Zon, L.I. (2008) Transparent Adult Zebrafish as a Tool for In Vivo Transplantation Analysis. Cell Stem Cell. 2(2):183-189
Lord, A.M., North, T.E., and Zon, L.I. (2007) Prostaglandin E2: Making More of Your Marrow. Cell cycle (Georgetown, Tex.). 6(24):3054-3057
Goessling, W., North, T.E., and Zon, L.I. (2007) Ultrasound biomicroscopy permits in vivo characterization of zebrafish liver tumors. Nature Methods. 4(7):551-553
North, T.E., Goessling, W., Walkley, C.R., Lengerke, C., Kopani, K.R., Lord, A.M., Weber, G.J., Bowman, T.V., Jang, I.H., Grosser, T., Fitzgerald, G.A., Daley, G.Q., Orkin, S.H., and Zon, L.I. (2007) Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature. 447(7147):1007-1011
Goessling, W., North, T.E., and Zon, L.I. (2007) New waves of discovery: modeling cancer in zebrafish. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 25(17):2473-2479
Polok, B. (2007) Analysis of Pou5f1 (Oct4) function during early zebrafish development. Ph.D. Thesis. :100p
Simons, M., Gloy, J., Ganner, A., Bullerkotte, A., Bashkurov, M., Kronig, C., Schermer, B., Benzing, T., Cabello, O.A., Jenny, A., Mlodzik, M., Polok, B., Driever, W., Obara, T., and Walz, G. (2005) Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nature Genetics. 37(5):537-543