FADD deficiency impairs early hematopoiesis in the bone marrow.
Signal transduction mediated by Fas-associated death domain protein (FADD) represents a paradigm of coregulation of apoptosis and cellular proliferation. During apoptotic signaling induced by death receptors including Fas, FADD is required for the recruitment and activation of caspase 8. In addition, a death receptor-independent function of FADD is essential for embryogenesis. In previous studies, FADD deficiency in embryonic stem cells resulted in a complete lack of B cells and dramatically reduced T cell numbers, as shown by Rag1(-/-) blastocyst complementation assays. However, T-specific FADD-deficient mice contained normal numbers of thymocytes and slightly reduced peripheral T cell numbers, whereas B cell-specific deletion of FADD led to increased peripheral B cell numbers. It remains undetermined what impact an FADD deficiency has on hematopoietic stem cells and progenitors. The current study analyzed the effect of simultaneous deletion of FADD in multiple cell types, including bone marrow cells, by using the IFN-inducible Mx1-cre transgene. The resulting FADD mutant mice did not develop lymphoproliferation diseases, unlike Fas-deficient mice. Instead, a time-dependent depletion of peripheral FADD-deficient lymphocytes was observed. In the bone marrow, a lack of FADD led to a dramatic decrease in the hematopoietic stem cells and progenitor-enriched population. Furthermore, FADD-deficient bone marrow cells were defective in their ability to generate lymphoid, myeloid, and erythroid cells. Thus, the results revealed a temporal requirement for FADD. Although dispensable during lymphopoiesis post lineage commitment, FADD plays a critical role in early hematopoietic stages in the bone marrow.
Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Stephen
S
Rosenberg
Haibing
H
Zhang
Jianke
J
Zhang
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D015672:Erythroid Precursor Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053200:Fas-Associated Death Domain Protein / Q000172:deficiency* / Q000235:genetics*; D019204:GTP-Binding Proteins / Q000235:genetics; D017353:Gene Deletion; D049452:Green Fluorescent Proteins / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics* / Q000276:immunology*; D019426:Integrases / Q000235:genetics; D008212:Lymphocyte Depletion / Q000379:methods*; D054503:Lymphoid Progenitor Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023461:Myeloid Progenitor Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D064547:Myxovirus Resistance Proteins; D013997:Time Factors; D019014:fas Receptor / Q000172:deficiency / Q000235:genetics
C505534:Fadd protein, mouse; C491899:Fas protein, mouse; D053200:Fas-Associated Death Domain Protein; C579070:Mx1 protein, mouse; D064547:Myxovirus Resistance Proteins; D019014:fas Receptor; D049452:Green Fluorescent Proteins; C045073:Cre recombinase; D019426:Integrases; D019204:GTP-Binding Proteins