Document Detail


Live imaging of neutrophil motility in a zebrafish model of WHIM syndrome.
MedLine Citation:
PMID:  20592249     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Kevin B Walters; Julie M Green; Jill C Surfus; Sa Kan Yoo; Anna Huttenlocher
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-06-30
Journal Detail:
Title:  Blood     Volume:  116     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-15     Completed Date:  2010-11-05     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2803-11     Citation Subset:  AIM; IM    
Affiliation:
Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI, USA.
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MeSH Terms
Descriptor/Qualifier:
Agammaglobulinemia / 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:
GM074827/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Chemokine CXCL12; 0/Receptors, CXCR4; 0/Zebrafish Proteins
Comments/Corrections
Comment In:
Blood. 2010 Oct 14;116(15):2621-2   [PMID:  20947686 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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