| Live imaging of neutrophil motility in a zebrafish model of WHIM syndrome. | |
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MedLine Citation:
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PMID: 20592249 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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CXCR4 is a G protein-coupled chemokine receptor that has been implicated in the pathogenesis of primary immunodeficiency disorders and cancer. Autosomal dominant gain-of-function truncations of CXCR4 are associated with warts, hypo-gammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a primary immunodeficiency disorder characterized by neutropenia and recurrent infections. Recent progress has implicated CXCR4-SDF1 (stromal cell-derived factor 1) signaling in regulating neutrophil homeostasis, but the precise role of CXCR4-SDF1 interactions in regulating neutrophil motility in vivo is not known. Here, we use the optical transparency of zebrafish to visualize neutrophil trafficking in vivo in a zebrafish model of WHIM syndrome. We demonstrate that expression of WHIM mutations in zebrafish neutrophils induces neutrophil retention in hematopoietic tissue, impairing neutrophil motility and wound recruitment. The neutrophil retention signal induced by WHIM truncation mutations is SDF1 dependent, because depletion of SDF1 with the use of morpholino oligonucleotides restores neutrophil chemotaxis to wounds. Moreover, localized activation of a genetically encoded, photoactivatable Rac guanosine triphosphatase is sufficient to direct migration of neutrophils that express the WHIM mutation. The findings suggest that this transgenic zebrafish model of WHIM syndrome may provide a valuable tool to screen for agents that modify CXCR4-SDF1 retention signals. |
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Authors:
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Kevin B Walters; Julie M Green; Jill C Surfus; Sa Kan Yoo; Anna Huttenlocher |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-06-30 |
Journal Detail:
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Title: Blood Volume: 116 ISSN: 1528-0020 ISO Abbreviation: Blood Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-10-15 Completed Date: 2010-11-05 Revised Date: 2011-10-14 |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 2803-11 Citation Subset: AIM; IM |
Affiliation:
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Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Agammaglobulinemia
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genetics Amino Acid Sequence Animals Animals, Genetically Modified Cell Movement Chemokine CXCL12 / genetics Chemotaxis, Leukocyte Disease Models, Animal Gene Expression Hematopoiesis Humans Immunologic Deficiency Syndromes / genetics, pathology Molecular Sequence Data Mutation Neutropenia / genetics*, pathology* Neutrophils / pathology, physiology* Receptors, CXCR4 / genetics Signal Transduction Syndrome Zebrafish Zebrafish Proteins / genetics |
| Grant Support | |
ID/Acronym/Agency:
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GM074827/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Chemokine CXCL12; 0/Receptors, CXCR4; 0/Zebrafish Proteins |
| Comments/Corrections | |
Comment In:
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Blood. 2010 Oct 14;116(15):2621-2
[PMID:
20947686
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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