title: Genetic variation responsible for mouse strain differences in integrin alpha 2 expression is associated with altered platelet responses to collagen.
abstract: As mouse models have become commonplace for studying hemostasis and thrombosis, we considered whether the mouse system had utility for assessing genetic alterations in platelet receptors. Platelets from 5 mouse strains (C57BL/6 [C57], FVB/N [FVB], BALB/c, C3H/He, and 129Sv) showed only minor differences in the expression of integrin alpha(IIb), integrin beta(3), glycoprotein (GP) Ib alpha, or GPVI across strains. However, FVB platelets expressed approximately 50% the level of integrin alpha(2) as platelets from other strains (P <.0001). We bred FVB mice with C57 and assessed alpha(2) expression in FVB/C57xFVB/C57 (F2) offspring. Linkage analysis demonstrated the gene responsible for alpha(2) levels is tightly linked to the D13mit260 marker (log odds [lod] score 6.7) near the alpha(2) gene. FVB platelets showed reduced aggregation and a longer lag phase to collagen. FVB and C57 platelets aggregated similarly to collagen-related peptide, but FVB platelets showed a reduction in rhodocytin-induced Syk and PLC gamma 2 tyrosine phosphorylation. Thus, FVB platelets express half the level of alpha(2) as other mouse strains, a trait linked to the alpha(2) gene and seemingly responsible for reduced platelet aggregation to collagen. These strain differences serve as a useful model for the 2-fold difference in human platelet alpha(2)beta(1) expression and demonstrate that alpha(2)beta(1) participates in signaling during platelet activation.
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Tong-Tong
authors.initials: TT
authors.lastname: Li
authors.forename: Susana
authors.initials: S
authors.lastname: Larrucea
authors.forename: Shiloe
authors.initials: S
authors.lastname: Souza
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
authors.forename: José A
authors.initials: JA
authors.lastname: López
authors.forename: Edward M
authors.initials: EM
authors.lastname: Rubin
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.forename: Paul F
authors.initials: PF
authors.lastname: Bray
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000737:chemistry / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology*; D004792:Enzyme Precursors / Q000378:metabolism; D008040:Genetic Linkage; D014644:Genetic Variation; D039421:Integrin alpha2 / Q000235:genetics* / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D051966:Phospholipase C gamma; D010766:Phosphorylation; D010974:Platelet Aggregation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D004792:Enzyme Precursors; D039421:Integrin alpha2; D047908:Intracellular Signaling Peptides and Proteins; D003094:Collagen; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D010738:Type C Phospholipases; D051966:Phospholipase C gamma