An essential function of FADD in hematopoietic stem cells and progenitors (36.10)

Abstract

Abstract Signal transduction mediated by FADD represents a paradigm of co-regulation of both apoptosis and proliferation. Death receptors signal through FADD to activate the downstream caspase 8, and are required for homeostasis in the immune system, yet dispensable during embryonic development. In contrast, a FADD deficiency results in embryonic lethality. In previous studies, a lack of FADD in embryonic stem cells led to severe defects in lymphocyte development. However, conditional deletion of FADD following lymphoid lineage commitment still allows for the generation of T and B cell compartments. Whereas Fas-mediated apoptosis is blocked, a lymphoproliferation disease is lacking in lymphocyte-specific FADD-deficient mice due in part to defective lymphocyte activation. Recent studies indicated that a loss of Fas in dendritic cells is sufficient to cause lymphoproliferation diseases, while the impact of a FADD deficiency in non-lymphiod cells has not been determined. The current study analyzed the effect of simultaneous deletion of FADD in multiple cell types in adult mice by using the IFN-inducible MX1-Cre transgene. Unlike Fas deficient mice, the resulting FADD mutant mice do not develop lymphoproliferation diseases. However, the data demonstrated that FADD plays a critical role in the differentiation and maintenance of hematopoietic stem cells and progenitors.