Targeted Disruption of the Mouse Gz-alpha Gene: A Role for Gz in Platelet Function?

Kim L. Kelleher; Klaus I. Matthaei

doi:10.1055/s-0037-1615616

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2001; 85(03): 529-532
DOI: 10.1055/s-0037-1615616

Review Article

Schattauer GmbH

Targeted Disruption of the Mouse G_z-alpha Gene: A Role for G_z in Platelet Function?

Kim L. Kelleher

¹Division of Neuroscience

,

Klaus I. Matthaei

²Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, Australia

› Institutsangaben

Abstract

Summary

G_z is one of nine G proteins identified in platelets and its role in these cells is unknown. Our laboratory has generated a mouse deficient in the G_z-alpha gene in the hope of determining its in vivo function. Bleeding times from the tail tip of G_zα deficient mice was significantly longer than wild type mice. Platelet aggregation and ATP secretion did not differ between wild type and G_zα deficient mice. When mice were presented with a thromboembolism challenge no differences were observed in the survival or mortality of wild type or G_zα deficient mice, however a strain difference was observed. Ignoring the genetic background of a mutant mouse might lead to a misinterpretation of results and thus it is absolutely critical to take the genetic background into account when assessing any aspect of a mutant mouse.

Keywords

G proteins - genetically mutant mice - ATP secretion - platelet aggregation - thromboembolism

Volltext

Referenzen

References
1 Brass LF, Hoxie JA, Manning DR. Signaling through G proteins and G protein-coupled receptors during platelet activation. Thromb Haemost 1993; 70: 217-23.
2 Matsuoka M, Itoh H, Kozasa T, Kaziro Y. Sequence analysis of cDNA and genomic DNA for a putative pertussis toxin-insensitive guanine nucleotide-binding regulatory protein alpha subunit. Proc Natl Acad Sci USA 1988; 85: 5384-8.
3 Fong HK, Yoshimoto KK, Eversole-Cire P, Simon MI. Identification of a GTP-binding protein alpha subunit that lacks an apparent ADP-ribosylation site for pertussis toxin. Proc. Natl. Acad. Sci. USA 1988; 85: 3066-70.
4 Fields TA, and Casey PJ. Signalling functions and biochemical properties of pertussis toxin-resistant G-proteins. Biochem. J 1997; 321: 561-71.
5 Offermanns S, Toombs CF, Hu YH, Simon MI. Defective platelet activation in G alpha(q)-deficient mice. Nature 1997; 389: 183-6.
6 Simonds WF. G protein regulation of adenylate cyclase. Trends Pharmacol. Sci. 1999; 20: 66-73.
7 Klages B, Brandt U, Simon MI, Schultz G, Offermanns S. Activation of G12/G13 results in shape change and Rho/Rho-kinase- mediated myosin light chain phosphorylation in mouse platelets. J Cell. Biol. 1999; 144: 745-54.
8 Ledermann B, and Burki K. Establishment of a germ-line competent C57BL/6 embryonic stem cell line. Exp. Cell. Res. 1991; 197: 254-8.
9 Thomas KR, and Capecchi MR. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell 1987; 51: 503-12.
10 Mansour SL, Thomas KR, Capecchi MR. Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes. Nature 1988; 336: 348-52.
11 Nitschke L, Kopf M, Lamers MC. Quick nested PCR screening of ES cell clones for gene targeting events. Biotechniques 1993; 14: 914-6.
12 DiMinno G, and Silver MJ. Mouse antithrombotic assay: a simple method for the evaluation of antithrombotic agents in vivo. Potentiation of anti-thrombotic activity by ethyl alcohol. J Pharmacol Exp Ther 1983; 225: 57-60.
13 Rosenblum WI, Nelson GH, Cockrell CS, Ellis EF. Some properties of mouse platelets. Thromb. Res. 1983; 30: 347-55.
14 Brusa R. Genetically modified mice in neuropharmacology. Pharmacol. Res. 1999; 39: 405-19.
15 Matsusaka T, Fogo A, Ichikawa I. Targeting the genes of angiotensin receptors. Semin. Nephrol. 1997; 17: 396-403.
16 Blendy JA, Kaestner KH, Schmid W, Gass P, Schutz G. Targeting of the CREB gene leads to up-regulation of a novel CREB mRNA isoform. EMBO J 1996; 15: 1098-106.
17 Faraci FM, and Sigmund CD. Vascular biology in genetically altered mice. Smaller vessels, bigger insight. Circ. Res. 1999; 85: 1214-25.
18 Ui M. Islet-activating protein, pertussis toxin: a probe for functions of the inhibitory guanine nucleotide regulatory component of adenylate cyclase. Trends Pharmacol Sci 1984; 5: 277-9.
19 Lapetina EG, Reep B, Chang KJ. Treatment of human platelets with trypsin, thrombin, or collagen inhibits the pertussis toxin-induced ADPribosylation of a 41-kDa protein. Proc. Natl. Acad. Sci. USA 1986; 83: 5880-3.
20 Mutant mice and neuroscience: recommendations concerning genetic background.. Banbury Conference on genetic background in mice. Neuron 1997; 19: 755-9.