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Title: Genetic variation responsible for mouse strain differences in integrin {alpha}{sub 2} expression is associated with altered platelet responses to collagen

Abstract

Formation of a thrombus at the site of an injured vessel requires the coordinated action of critical platelet plasma membrane adhesion molecules. The most important initial contact of platelets with the exposed endothelial collagen and von Willebrand factor (VWF) involves the binding of glycoprotein (GP) Ib{alpha} to immobilized VWF. The VWF-GPIb{alpha} interaction is ''fast-on'' and relatively ''fast-off,'' and results in a rolling of platelets along the exposed subendothelium. This slowing of the platelets allows binding of the activating collagen-receptor, GPVI, to its ligand, resulting in activation of platelet integrins and subsequent firm adhesion, where the reactions between receptor and ligand are relatively ''slow-on'' but irreversible. The binding of integrin {alpha}{sub 2} {beta}{sub 1} underlying firm adhesion. Intracellular signaling between and through these adhesive receptors plays a crucial role in platelet adhesion and aggregation. The importance of the GPIb-IX-V and {alpha}{sub IIb} {beta}{sub 3} in normal hemostasis is under scored by the bleeding diatheses that have been reported in patients with quantitative or qualitative deficiencies of the genes that encode them. Mouse models are now commonplace for studying hemostasis and thrombosis, and important insights pertaining to the major platelet adhesive receptors have been gleaned from mouse studies involving targeted disruptions ofmore » the genes for GPIb{alpha}, GPVI, and integrin chains 2,9,10 1,4 IIb 11 and 3.12 A variety of different mouse strains have been used to assess hemostasis. For example, the FVB strain is typically used for transgenic experiments, the 129/Sv strain is used to derive embryonic stem (ES) cells, and the C57 strain is used for uniform background breeding studies. Different strains may exhibit different levels of gene expression, a feature that has been used to elucidate crucial gene regions regulating transcription. We and others have previously studied how genetic changes exert quantitative and qualitative alterations in human platelet adhesive receptors. Polymorphisms of both integrin {alpha}{sub 2} and GPIb have been associated with quantitative differences in receptor levels in healthy individuals. The variation of integrin {alpha}{sub 2} in the normal population is 5-fold, and some portion of this variability has been associated with a C/T polymorphism at nucleotide 807. Individuals homozygous for the 807C or 807T alleles have an average 2-fold difference in platelet {alpha}{sub 2} {beta}{sub 1} levels, and this difference has been linked to increased adhesion to collagen and clinical thrombotic events. Comparable alterations in platelet adhesion receptor expression have not been assessed in different mouse strains. Assessing the functional consequences of subtle genetic variations in humans is challenged by numerous gene-gene and gene environment interactions, and studies in mice can greatly minimize these confounding variables. In addition, comparative sequence analyses between species and between nonhuman primates have proved useful for identifying sequences that affect function and expression. Thus, in the case of platelet adhesion receptors, knowing mouse strain differences in expression levels might be valuable for defining the responsible quantitative trait loci as well as affecting strain choice for particular functional experiments.« less

Authors:
; ; ; ; ; ; ;
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE.Office of Management Budget and Evaluation; National Institutes of Health Grant HL65229, National Heart Lung and Blood Institute Grant HL66728; Fondren Foundation (US)
OSTI Identifier:
834235
Report Number(s):
LBNL-55333
Journal ID: ISSN 0006-4971; BLOOAW; R&D Project: GHPG6A; TRN: US200432%%212
DOE Contract Number:  
AC03-76SF00098
Resource Type:
Journal Article
Journal Name:
Blood
Additional Journal Information:
Journal Volume: 103; Journal Issue: 9; Other Information: Journal Publication Date: 1 MAY 2004; PBD: 1 Nov 2003; Journal ID: ISSN 0006-4971
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ADHESION; ADHESIVES; BREEDING; COLLAGEN; FUNCTIONALS; GENES; GENETICS; GLYCOPROTEINS; MEMBRANES; MICE; NUCLEOTIDES; PATIENTS; PLASMA; PRIMATES; STRAINS; THROMBOSIS; TRANSCRIPTION

Citation Formats

Li, Tong-Tong, Larrucea, Susana, Souza, Shiloe, Leal, Suzanne M, Lopez, Jose A, Rubin, Edward M, Nieswandt, Bernhard, and Bray, Paul F. Genetic variation responsible for mouse strain differences in integrin {alpha}{sub 2} expression is associated with altered platelet responses to collagen. United States: N. p., 2003. Web.
Li, Tong-Tong, Larrucea, Susana, Souza, Shiloe, Leal, Suzanne M, Lopez, Jose A, Rubin, Edward M, Nieswandt, Bernhard, & Bray, Paul F. Genetic variation responsible for mouse strain differences in integrin {alpha}{sub 2} expression is associated with altered platelet responses to collagen. United States.
Li, Tong-Tong, Larrucea, Susana, Souza, Shiloe, Leal, Suzanne M, Lopez, Jose A, Rubin, Edward M, Nieswandt, Bernhard, and Bray, Paul F. Sat . "Genetic variation responsible for mouse strain differences in integrin {alpha}{sub 2} expression is associated with altered platelet responses to collagen". United States.
@article{osti_834235,
title = {Genetic variation responsible for mouse strain differences in integrin {alpha}{sub 2} expression is associated with altered platelet responses to collagen},
author = {Li, Tong-Tong and Larrucea, Susana and Souza, Shiloe and Leal, Suzanne M and Lopez, Jose A and Rubin, Edward M and Nieswandt, Bernhard and Bray, Paul F},
abstractNote = {Formation of a thrombus at the site of an injured vessel requires the coordinated action of critical platelet plasma membrane adhesion molecules. The most important initial contact of platelets with the exposed endothelial collagen and von Willebrand factor (VWF) involves the binding of glycoprotein (GP) Ib{alpha} to immobilized VWF. The VWF-GPIb{alpha} interaction is ''fast-on'' and relatively ''fast-off,'' and results in a rolling of platelets along the exposed subendothelium. This slowing of the platelets allows binding of the activating collagen-receptor, GPVI, to its ligand, resulting in activation of platelet integrins and subsequent firm adhesion, where the reactions between receptor and ligand are relatively ''slow-on'' but irreversible. The binding of integrin {alpha}{sub 2} {beta}{sub 1} underlying firm adhesion. Intracellular signaling between and through these adhesive receptors plays a crucial role in platelet adhesion and aggregation. The importance of the GPIb-IX-V and {alpha}{sub IIb} {beta}{sub 3} in normal hemostasis is under scored by the bleeding diatheses that have been reported in patients with quantitative or qualitative deficiencies of the genes that encode them. Mouse models are now commonplace for studying hemostasis and thrombosis, and important insights pertaining to the major platelet adhesive receptors have been gleaned from mouse studies involving targeted disruptions of the genes for GPIb{alpha}, GPVI, and integrin chains 2,9,10 1,4 IIb 11 and 3.12 A variety of different mouse strains have been used to assess hemostasis. For example, the FVB strain is typically used for transgenic experiments, the 129/Sv strain is used to derive embryonic stem (ES) cells, and the C57 strain is used for uniform background breeding studies. Different strains may exhibit different levels of gene expression, a feature that has been used to elucidate crucial gene regions regulating transcription. We and others have previously studied how genetic changes exert quantitative and qualitative alterations in human platelet adhesive receptors. Polymorphisms of both integrin {alpha}{sub 2} and GPIb have been associated with quantitative differences in receptor levels in healthy individuals. The variation of integrin {alpha}{sub 2} in the normal population is 5-fold, and some portion of this variability has been associated with a C/T polymorphism at nucleotide 807. Individuals homozygous for the 807C or 807T alleles have an average 2-fold difference in platelet {alpha}{sub 2} {beta}{sub 1} levels, and this difference has been linked to increased adhesion to collagen and clinical thrombotic events. Comparable alterations in platelet adhesion receptor expression have not been assessed in different mouse strains. Assessing the functional consequences of subtle genetic variations in humans is challenged by numerous gene-gene and gene environment interactions, and studies in mice can greatly minimize these confounding variables. In addition, comparative sequence analyses between species and between nonhuman primates have proved useful for identifying sequences that affect function and expression. Thus, in the case of platelet adhesion receptors, knowing mouse strain differences in expression levels might be valuable for defining the responsible quantitative trait loci as well as affecting strain choice for particular functional experiments.},
doi = {},
journal = {Blood},
issn = {0006-4971},
number = 9,
volume = 103,
place = {United States},
year = {2003},
month = {11}
}