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Targeted disruption of guanosine diphosphate-dissociation inhibitor for
Rho-related proteins, GDID4: normal hematopoietic differentiation but
subtle defect in superoxide production by macrophages derived from in vitro
embryonal stem cell differentiation
JC Guillemot, BA Kruskal, CN Adra, S Zhu, JL Ko, P Burch, K Nocka, K Seetoo, E Simons and B Lim
Division of Hematology/Oncology, Beth Israel Hospital, Harvard Medical
School, Boston, MA, USA.
The Rho subfamily of small guanosine triphosphate (GTP)-binding proteins,
through their role in cytoskeletal organization, is involved in diverse
cellular functions, including cell motility and morphologic changes during
differentiation. Rac also has a special role in the production of
superoxide, a key component in phagocytic antimicrobial function. Guanosine
diphosphate (GDP)-dissociation inhibitors (GDIs) belong to one of three
classes of proteins that regulate the critical cycling of GTP-binding
proteins between the inactive and active states. Two homologous GDIs for
the Rho subfamily have been identified. GDID4 is preferentially expressed
in hematopoietic cells, while RhoGDI is ubiquitously expressed. Whether
different physiologic functions are subserved by the two GDIs is unknown.
We have derived embryonal stem (ES) cells with targeted disruption of both
alleles of the GDID4 gene and examined hematopoiesis and phagocytic
functions of macrophages derived from in vitro ES-cell differentiation.
GDID4-/- ES cells develop like wild-type cells into colonies that contain
heterogeneous populations of progenitor cells and differentiated
erythromyeloid cells. GDID4-/- cells express no GDID4 protein, but have
normal levels of RhoGDI. GDID4-/- macrophages phagocytose yeasts and
antibody- opsonized erythrocytes as effectively as wild-type macrophages.
However, a slight but consistent reduction in their capacity to generate
superoxide was observed, which suggests new insight into the cellular role
of GDID4. The minimal phenotypic effect of a loss of function of GDID4 also
indicates a significant redundancy of function between GDID4 and RhoGDI.
Their functional repertoire may be better revealed by a disruption of both
genes. The use of hematopoietic cells derived in vitro from genotypically
altered ES cells avoids the difficulties inherent in generating knockout
animals and is a useful complementary approach for evaluating the gene
function.
Volume 88,
Issue 7,
pp. 2722-2731,
10/01/1996
Copyright © 1996 by The American Society of Hematology
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