Macrophages play an essential role in the resolution of tissue damage through removal of necrotic cells, thus paving the way for tissue regeneration. Macrophages also directly support the formation of new tissue to replace the injury, through their acquisition of an anti-inflammatory, or M2, phenotype, characterized by a gene expression program that includes IL-10, the IL-13 receptor, and arginase 1. We report that deletion of two CREB-binding sites from theCebpbpromoter abrogatesCebpbinduction upon macrophage activation. This blocks the downstream induction of M2-specificMsr1,Il10,II13ra, andArg-1genes, whereas the inflammatory (M1) genesIl1,Il6,Tnfa, andIl12are not affected. Mice carrying the mutatedCebpbpromoter (βΔCre) remove necrotic tissue from injured muscle, but exhibit severe defects in muscle fiber regeneration. Conditional deletion of theCebpbgene in muscle cells does not affect regeneration, showing that the C/EBPβ cascade leading to muscle repair is muscle-extrinsic. While βΔCre macrophages efficiently infiltrate injured muscle they fail to upregulateCebpb, leading to decreasedArg-1expression. CREB-mediated induction ofCebpbexpression is therefore required in infiltrating macrophages for upregulation of M2-specific genes and muscle regeneration, providing a direct genetic link between these two processes.

The Ikaros gene encodes a zinc‐finger transcription factor required during early B cell development, as B‐lineage cells are absent in mice lacking Ikaros. Here we describe a novel Ikaros‐targeted mouse line carrying a β‐galactosidase reporter in which low amounts of Ikaros proteins remain expressed. In homozygote animals, B cells are absent during fetal development, but develop postnatally from a reduced pool of precursors. In vitro, the proliferation and differentiation of B‐lineage progenitors are severely impaired. These defects are attenuated in vivo, but bone marrow B cells display an unusual pattern of cell surface marker expression and show decreased transcript levels for TdT, Rag‐1, Rag‐2 and λ5. These abnormalities suggest a partial block atthe proB cell stage of differentiation. In the periphery, mature B cells exhibit a lower activation threshold but form fewer germinal centers in response to antigenic stimulation. Our results show that Ikaros controls multiple aspects of B cell differentiation and function.

The Ikaros transcription factor is both a key regulator of lymphocyte differentiation and a tumor suppressor in T lymphocytes. Mice carrying a hypomorphic mutation (Ik^L/L) in the Ikaros gene all develop thymic lymphomas. Ik^L/L tumors always exhibit strong activation of the Notch pathway, which is required for tumor cell proliferation in vitro. Notch activation occurs early in tumorigenesis and may precede transformation, as ectopic expression of the Notch targets Hes-1 and Deltex-1 is detected in thymocytes from young Ik^L/L mice with no overt signs of transformation. Notch activation is further amplified by secondary mutations that lead to C-terminal truncations of Notch 1. Strikingly, restoration of Ikaros activity in tumor cells leads to a rapid and specific downregulation of Notch target gene expression and proliferation arrest. Furthermore, Ikaros binds to the Notch-responsive element in the Hes-1 promoter and represses Notch-dependent transcription from this promoter. Thus, Ikaros-mediated repression of Notch target gene expression may play a critical role in defining the tumor suppressor function of this factor.