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Blood, 1 October 2001, Vol. 98, No. 7, pp. 2248-2255
RED CELLS
GATA1-Cre mediates Piga gene inactivation in the
erythroid/megakaryocytic lineage and leads to circulating red cells
with a partial deficiency in glycosyl phosphatidylinositol-linked
proteins (paroxysmal nocturnal hemoglobinuria type II
cells)
Marek Jasinski,
Peter Keller,
Yuko Fujiwara,
Stuart H. Orkin, and
Monica Bessler
From the Division of Hematology, Department of Internal
Medicine, Washington University School of Medicine, St Louis, MO, and
the Howard Hughes Medical Institute, Harvard Medical School, Boston,
MA.
Patients with paroxysmal nocturnal hemoglobinuria (PNH) have blood
cells deficient in glycosyl phosphatidylinositol (GPI)-linked proteins
owing to a somatic mutation in the X-linked PIGA gene. To
target Piga recombination to the erythroid/megakaryocytic
lineage in mice, the Cre/loxP system was used, and Cre was
expressed under the transcriptional regulatory sequences of
GATA-1. Breeding of GATA1-cre (G) transgenic mice with mice
carrying a floxed Piga (L) allele was associated
with high embryonic lethality. However, double-transgenic (GL) mice
that escaped early recombination looked healthy and were observed for
16 months. Flow cytometric analysis of peripheral blood cells showed
that GL mice had up to 100% of red cells deficient in GPI-linked
proteins. The loss of GPI-linked proteins on the cell surface occurred
late in erythroid differentiation, causing a proportion of red cells to
express low residual levels of GPI-linked proteins. Red cells with
residual expression of GPI-linked proteins showed an intermediate
sensitivity toward complement and thus resemble PNH type II cells in
patients with PNH. Recombination of the floxed Piga allele
was also detected in cultured megakaryocytes, mast cells, and
eosinophils, but not in neutrophils, lymphocytes, or nonhematopoietic
tissues. In summary, GATA1-Cre causes high-efficiency Piga
gene inactivation in a GATA-1-specific pattern. For the first time,
mice were generated that have almost 100% of red cells deficient in
GPI-linked proteins. These animals will be valuable to further
investigate the consequences of GPI-anchor deficiency on
erythroid/megakaryocytic cells.
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