Genetic variation responsible for mouse strain differences in integrin alpha 2 expression is associated with altered platelet responses to collagen.
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.
Li
Tong-Tong
TT
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Larrucea
Susana
S
Souza
Shiloe
S
Leal
Suzanne M
SM
López
José A
JA
Rubin
Edward M
EM
Nieswandt
Bernhard
B
Bray
Paul F
PF
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
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