Submitted November 29, 2006
Accepted March 17, 2007
Abnormal hematopoiesis in Gab2 mutant mice
Yi Zhang, Ernesto Diaz-Flores, Geqiang Li, Zhengqi Wang, Zizhen Kang, Eleonora Haviernikova, Sara Rowe, Cheng-Kui Qu, William Tse, Kevin M Shannon, and Kevin D Bunting*
Department of Medicine, Division of Hematology/Oncology, Case Western Reserve University, School of Medicine, Cleveland, OH
Departments of Pediatrics and Medicine, Program in Developmental and Stem Cell Biology, University of California, San Francisco, CA
Case Comprehensive Cancer Center, Cleveland, OH
Center for Stem Cell and Regenerative Medicine, Cleveland, OH
* Corresponding author; email: kevin.bunting{at}case.edu.
Gab2 is an important adapter molecule for cytokine signaling. Despite its major role in signaling by receptors associated with hematopoiesis, the role of Gab2 in hematopoiesis has not been addressed. We report that despite normal numbers of peripheral blood cells, bone marrow cells, and c-Kit+Lin-Sca-1+ (KLS) cells, Gab2-deficient hematopoietic cells are deficient in cytokine responsiveness. Significant reductions in colony-form units in culture (CFU-C) in the presence of limiting cytokine concentrations were observed and these defects could be completely corrected by retroviral complementation. In earlier hematopoiesis, Gab2-deficient KLS cells isolated in vitro responded poorly to hematopoietic growth factors resulting in up to an 11-fold reduction in response to a cocktail of stem cell factor, flt3-ligand, and thrombopoietin. Gab2-deficient c-Kit+Lin- cells also demonstrate impaired activation of ERK and S6 in response to IL-3, which supports defects in activating the phosphatidylinositol-3 kinase and mitogen-associated protein kinase signaling cascades. Associated with the early defects in cytokine response, competitive transplant of Gab2-/- bone marrow cells resulted in defective long-term multilineage repopulation. Therefore, we demonstrate that Gab2 adapter function is intrinsically required for hematopoietic cell response to early-acting cytokines resulting in defective hematopoiesis in Gab2-deficient mice.
