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Hagedorn, Elliott

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Hagedorn

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Elliott

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Hagedorn, Elliott
Author's Publications: search.filters.isAuthorOfPublication.1e743db3-3a36-4544-b237-c41d2d5cc190

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Now showing 1 - 7 of 7
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    EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay
    (The Rockefeller University Press, 2017) Volpi, Stefano; Yamazaki, Yasuhiro; Brauer, Patrick M.; van Rooijen, Ellen; Hayashida, Atsuko; Slavotinek, Anne; Sun Kuehn, Hye; Di Rocco, Maja; Rivolta, Carlo; Bortolomai, Ileana; Du, Likun; Felgentreff, Kerstin; Ott de Bruin, Lisa; Hayashida, Kazutaka; Freedman, George; Marcovecchio, Genni Enza; Capuder, Kelly; Rath, Prisni; Luche, Nicole; Hagedorn, Elliott; Buoncompagni, Antonella; Royer-Bertrand, Beryl; Giliani, Silvia; Poliani, Pietro Luigi; Imberti, Luisa; Dobbs, Kerry; Poulain, Fabienne E.; Martini, Alberto; Manis, John; Linhardt, Robert J.; Bosticardo, Marita; Rosenzweig, Sergio Damian; Lee, Hane; Puck, Jennifer M.; Zúñiga-Pflücker, Juan Carlos; Zon, Leonard; Park, Pyong; Superti-Furga, Andrea; Notarangelo, Luigi D.
    We studied three patients with severe skeletal dysplasia, T cell immunodeficiency, and developmental delay. Whole-exome sequencing revealed homozygous missense mutations affecting exostosin-like 3 (EXTL3), a glycosyltransferase involved in heparan sulfate (HS) biosynthesis. Patient-derived fibroblasts showed abnormal HS composition and altered fibroblast growth factor 2 signaling, which was rescued by overexpression of wild-type EXTL3 cDNA. Interleukin-2–mediated STAT5 phosphorylation in patients’ lymphocytes was markedly reduced. Interbreeding of the extl3-mutant zebrafish (box) with Tg(rag2:green fluorescent protein) transgenic zebrafish revealed defective thymopoiesis, which was rescued by injection of wild-type human EXTL3 RNA. Targeted differentiation of patient-derived induced pluripotent stem cells showed a reduced expansion of lymphohematopoietic progenitor cells and defects of thymic epithelial progenitor cell differentiation. These data identify EXTL3 mutations as a novel cause of severe immune deficiency with skeletal dysplasia and developmental delay and underline a crucial role of HS in thymopoiesis and skeletal and brain development.
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    Unexpectedly uneven: posttransplant skeletal distribution of hematopoietic stem cell clones
    (The Rockefeller University Press, 2014) Hagedorn, Elliott; Zon, Leonard
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    A Sensitized Screen for Genes Promoting Invadopodia Function In Vivo: CDC-42 and Rab GDI-1 Direct Distinct Aspects of Invadopodia Formation
    (Public Library of Science, 2016) Lohmer, Lauren L.; Clay, Matthew R.; Naegeli, Kaleb M.; Chi, Qiuyi; Ziel, Joshua W.; Hagedorn, Elliott; Park, Jieun E.; Jayadev, Ranjay; Sherwood, David R.
    Invadopodia are specialized membrane protrusions composed of F-actin, actin regulators, signaling proteins, and a dynamically trafficked invadopodial membrane that drive cell invasion through basement membrane (BM) barriers in development and cancer. Due to the challenges of studying invasion in vivo, mechanisms controlling invadopodia formation in their native environments remain poorly understood. We performed a sensitized genome-wide RNAi screen and identified 13 potential regulators of invadopodia during anchor cell (AC) invasion into the vulval epithelium in C. elegans. Confirming the specificity of this screen, we identified the Rho GTPase cdc-42, which mediates invadopodia formation in many cancer cell lines. Using live-cell imaging, we show that CDC-42 localizes to the AC-BM interface and is activated by an unidentified vulval signal(s) that induces invasion. CDC-42 is required for the invasive membrane localization of WSP-1 (N-WASP), a CDC-42 effector that promotes polymerization of F-actin. Loss of CDC-42 or WSP-1 resulted in fewer invadopodia and delayed BM breaching. We also characterized a novel invadopodia regulator, gdi-1 (Rab GDP dissociation inhibitor), which mediates membrane trafficking. We show that GDI-1 functions in the AC to promote invadopodia formation. In the absence of GDI-1, the specialized invadopodial membrane was no longer trafficked normally to the invasive membrane, and instead was distributed to plasma membrane throughout the cell. Surprisingly, the pro-invasive signal(s) from the vulval cells also controls GDI-1 activity and invadopodial membrane trafficking. These studies represent the first in vivo screen for genes regulating invadopodia and demonstrate that invadopodia formation requires the integration of distinct cellular processes that are coordinated by an extracellular cue.
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    Distinct Roles for Matrix Metalloproteinases 2 and 9 in Embryonic Hematopoietic Stem Cell Emergence, Migration, and Niche Colonization
    (Elsevier, 2017) Theodore, Lindsay; Hagedorn, Elliott; Cortes, Mauricio; Natsuhara, Kelsey; Liu, Sarah Y.; Perlin, Julie; Yang, Song; Daily, Madeleine L.; Zon, Leonard; North, Trista
    Summary Hematopoietic stem/progenitor cells (HSPCs) are formed during ontogeny from hemogenic endothelium in the ventral wall of the dorsal aorta (VDA). Critically, the cellular mechanism(s) allowing HSPC egress and migration to secondary niches are incompletely understood. Matrix metalloproteinases (MMPs) are inflammation-responsive proteins that regulate extracellular matrix (ECM) remodeling, cellular interactions, and signaling. Here, inhibition of vascular-associated Mmp2 function caused accumulation of fibronectin-rich ECM, retention of runx1/cmyb+ HSPCs in the VDA, and delayed caudal hematopoietic tissue (CHT) colonization; these defects were absent in fibronectin mutants, indicating that Mmp2 facilitates endothelial-to-hematopoietic transition via ECM remodeling. In contrast, Mmp9 was dispensable for HSPC budding, being instead required for proper colonization of secondary niches. Significantly, these migration defects were mimicked by overexpression and blocked by knockdown of C-X-C motif chemokine-12 (cxcl12), suggesting that Mmp9 controls CHT homeostasis through chemokine regulation. Our findings indicate Mmp2 and Mmp9 play distinct but complementary roles in developmental HSPC production and migration.
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    Angiopoietin-like proteins stimulate HSPC development through interaction with notch receptor signaling
    (eLife Sciences Publications, Ltd, 2015) Lin, Michelle I; Price, Emily N; Boatman, Sonja; Hagedorn, Elliott; Trompouki, Eirini; Satishchandran, Sruthi; Carspecken, Charles W; Uong, Audrey; DiBiase, Anthony; Yang, Song; Canver, Matthew C.; Dahlberg, Ann; Lu, Zhigang; Zhang, Cheng Cheng; Orkin, Stuart; Bernstein, Irwin D; Aster, Jon C; White, Richard M; Zon, Leonard
    Angiopoietin-like proteins (angptls) are capable of ex vivo expansion of mouse and human hematopoietic stem and progenitor cells (HSPCs). Despite this intriguing ability, their mechanism is unknown. In this study, we show that angptl2 overexpression is sufficient to expand definitive HSPCs in zebrafish embryos. Angptl1/2 are required for definitive hematopoiesis and vascular specification of the hemogenic endothelium. The loss-of-function phenotype is reminiscent of the notch mutant mindbomb (mib), and a strong genetic interaction occurs between angptls and notch. Overexpressing angptl2 rescues mib while overexpressing notch rescues angptl1/2 morphants. Gene expression studies in ANGPTL2-stimulated CD34+ cells showed a strong MYC activation signature and myc overexpression in angptl1/2 morphants or mib restored HSPCs formation. ANGPTL2 can increase NOTCH activation in cultured cells and ANGPTL receptor interacted with NOTCH to regulate NOTCH cleavage. Together our data provide insight to the angptl-mediated notch activation through receptor interaction and subsequent activation of myc targets. DOI: http://dx.doi.org/10.7554/eLife.05544.001
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    Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits
    (2016) Pankratz, Nathan; Schick, Ursula M; Zhou, Yi; Zhou, Wei; Ahluwalia, Tarunveer Singh; Allende, Maria Laura; Auer, Paul L; Bork-Jensen, Jette; Brody, Jennifer A; Chen, Ming-Huei; Clavo, Vinna; Eicher, John D; Grarup, Niels; Hagedorn, Elliott; Hu, Bella; Hunker, Kristina; Johnson, Andrew D; Leusink, Maarten; Lu, Yingchang; Lyytikäinen, Leo-Pekka; Manichaikul, Ani; Marioni, Riccardo E; Nalls, Mike A; Pazoki, Raha; Smith, Albert Vernon; van Rooij, Frank J A; Yang, Min-Lee; Zhang, Xiaoling; Zhang, Yan; Asselbergs, Folkert W; Boerwinkle, Eric; Borecki, Ingrid B; Bottinger, Erwin P; Cushman, Mary; de Bakker, Paul I W; Deary, Ian J; Dong, Liguang; Feitosa, Mary F; Floyd, James S; Franceschini, Nora; Franco, Oscar H; Garcia, Melissa E; Grove, Megan L; Gudnason, Vilmundur; Hansen, Torben; Harris, Tamara B; Hofman, Albert; Jackson, Rebecca D; Jia, Jia; Kähönen, Mika; Launer, Lenore J; Lehtimäki, Terho; Liewald, David C; Linneberg, Allan; Liu, Yongmei; Loos, Ruth J F; Nguyen, Vy; Numans, Mattijs E; Pedersen, Oluf; Psaty, Bruce M; Raitakari, Olli T; Rich, Stephen S; Rivadeneira, Fernando; Di Sant, Amanda M Rosa; Rotter, Jerome I; Starr, John M; Taylor, Kent D; Thuesen, Betina Heinsbæk; Tracy, Russell P; Uitterlinden, Andre G; Wang, Jiansong; Wang, Judy; Dehghan, Abbas; Huo, Yong; Cupples, L Adrienne; Wilson, James G; Proia, Richard L; Zon, Leonard; O’Donnell, Christopher J; Reiner, Alex P; Ganesh, Santhi K
    Hematologic measures such as hematocrit and white blood cell (WBC) count are heritable and clinically relevant. Erythrocyte and WBC phenotypes were analyzed with Illumina HumanExome BeadChip genotypes in 52,531 individuals (37,775 of European ancestry; 11,589 African Americans; 3,167 Hispanic Americans) from 16 population-based cohorts. We then performed replication analyses of novel discoveries in 18,018 European American women and 5,261 Han Chinese. We identified and replicated four novel erythrocyte trait-locus associations (CEP89, SHROOM3, FADS2, and APOE) and six novel WBC loci for neutrophil count (S1PR4), monocyte count (BTBD8, NLRP12, and IL17RA), eosinophil count (IRF1), and total WBC (MYB). The novel association of a rare missense variant in S1PR4 supports the role of sphingosine-1-phosphate signaling in leukocyte trafficking and circulating neutrophil counts. Loss-of-function experiments of S1pr4 in mouse and zebrafish demonstrated phenotypes consistent with the association observed in humans and altered kinetics of neutrophil recruitment and resolution in response to tissue injury.
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    CXCR1 remodels the vascular niche to promote hematopoietic stem and progenitor cell engraftment
    (The Rockefeller University Press, 2017) Blaser, Bradley W.; Moore, Jessica L.; Hagedorn, Elliott; Li, Brian; Riquelme, Raquel; Lichtig, Asher; Yang, Song; Zhou, Yi; Tamplin, Owen J.; Binder, Vera; Zon, Leonard
    The microenvironment is an important regulator of hematopoietic stem and progenitor cell (HSPC) biology. Recent advances marking fluorescent HSPCs have allowed exquisite visualization of HSPCs in the caudal hematopoietic tissue (CHT) of the developing zebrafish. Here, we show that the chemokine cxcl8 and its receptor, cxcr1, are expressed by zebrafish endothelial cells, and we identify cxcl8/cxcr1 signaling as a positive regulator of HSPC colonization. Single-cell tracking experiments demonstrated that this is a result of increases in HSPC–endothelial cell “cuddling,” HSPC residency time within the CHT, and HSPC mitotic rate. Enhanced cxcl8/cxcr1 signaling was associated with an increase in the volume of the CHT and induction of cxcl12a expression. Finally, using parabiotic zebrafish, we show that cxcr1 acts HSPC nonautonomously to improve the efficiency of donor HSPC engraftment. This work identifies a mechanism by which the hematopoietic niche remodels to promote HSPC engraftment and suggests that cxcl8/cxcr1 signaling is a potential therapeutic target in patients undergoing hematopoietic stem cell transplantation.