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Blood, 15 August 2000, Vol. 96, No. 4, pp. 1399-1408
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Thrombasthenic mice generated by replacement of the integrin
 IIb gene: demonstration that transcriptional activation
of this megakaryocytic locus precedes lineage commitment
Diana Tronik-Le Roux,
Valérie Roullot,
Christel Poujol,
Thierry Kortulewski,
Paquita Nurden, and
Gérard Marguerie
From the Département de Radiobiologie et
Radiopathologie, Commissariat à l'Energie Atomique, Evry Cedex,
and the Laboratoire d'Hemobiologie, Hôpital Cardiologique,
Pessac, France.
To analyze the transcriptional activity of the gene encoding the
 subunit of the platelet integrin IIb 3
during the hematopoietic differentiation, mice were produced in which
the herpes virus thymidine kinase (tk) was introduced in this
megakaryocytic specific locus using homologous recombination
technology. This provided a convenient manner in which to induce the
eradication of particular hematopoietic cells expressing the targeted
gene. Results of progenitor cell cultures and long-term bone marrow
(BM) assays showed that the growth of a subset of stem cells was
reduced in the presence of the antiherpetic drug ganciclovir,
demonstrating that the activation of the toxic gene occurs before the
commitment to the megakaryocytic lineage. Furthermore the
knock-in of the tk gene into the IIb locus
resulted in the knock-out of the IIb gene in
homozygous mice. Cultures of BM cells of these animals, combined with
ultrastructural analysis, established that the IIb
glycoprotein is dispensable for lineage commitment and megakaryocytic
maturation. Platelets collected from IIb-deficient mice
failed to bind fibrinogen, to aggregate, and to retract a fibrin clot.
Moreover, platelet -granules did not contain fibrinogen. Consistent
with these characteristics, the mice displayed bleeding disorders
similar to those in humans with Glanzmann thrombasthenia.
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