The canonical Wnt signaling pathway plays key roles in stem-cell maintenance, progenitor cell expansion, and lineage decisions. Transcriptional responses induced by Wnt depend on the association of either ␤-catenin or ␥-catenin with lymphoid enhancer factor/T cell factor transcription factors. Here we show that hematopoiesis, including thymopoiesis, is normal in the combined absence of ␤- IntroductionThe function and the hierarchical organization of the hematopoietic system depend on the unique ability of rare hematopoietic stem cells (HSCs) to self-renew and to give rise to committed progenitors, which will generate all blood cell lineages. Our understanding of the control mechanisms, which govern the balance of proliferation and differentiation of HSCs, is crucial for the development of therapies in areas such as bone marrow transplantation and the treatment of leukemia.The canonical Wnt signaling pathway plays a key role in stem-cell maintenance, expansion of committed progenitor cells, and control of lineage decisions in a variety of tissues, including the hematopoietic system. 1 ␤-Catenin is the central molecule in the canonical Wnt signaling pathway, which is tightly regulated at the level of protein stability. ␤-Catenin transmits the Wnt signal into the nucleus, where it acts as transcriptional coactivator by binding to members of the lymphoid enhancer factor/T cell factor (LEF/TCF) family of transcription factors. The related molecule ␥-catenin/plakoglobin can fulfill similar functions and activate target genes on Wnt signaling. 2 Deregulation of canonical Wnt signaling by aberrant stabilization of ␤-catenin is linked to a range of diseases including various cancers, whereas ectopic expression of ␥-catenin has been linked to acute myeloid leukemias. 3,4 Several reports have implicated Wnt signaling in HSC expansion and demonstrated responsiveness of HSCs to Wnt signals. 5,6 Conversely, deletion of Wnt genes or the Wnt receptor Fzd9 affects T-and/or B-cell development 7,8 and transgenic or retroviral expression of inhibitors of canonical Wnt signaling such as axin or dkk1 further indicated an important function of this pathway in hematopoiesis and thymopoiesis. 5,9,10 Individual gene ablations of LEF-1 and TCF-1 transcription factors displayed phenotypes in B-, T-, and NK-cell development. 11-13 TCF-1 deficiency resulted in incomplete blocks within the CD4 Ϫ CD8 Ϫ (DN) compartment of early thymocyte development and at the transition from immature single positive (ISP) to the CD4 ϩ CD8 ϩ (DP) stage. 11,14-16 LEF-1-deficiency aggravated the phenotype of mice with a hypomorphic TCF-1 allele, 17 demonstrating that the 2 factors play to some degree redundant functions during T-cell development. However, a complete block of Wnt signaling in the hematopoietic system has not been analyzed and results obtained by individual gene ablations of the 2 known signal transmitters ␤-and ␥-catenin have thus far failed to support a critical role of this pathway in hematopoiesis. 16,18,19 Strikingly, a genetic complementati...

Natural killer (NK) cells show enhanced functional competence when they express inhibitory receptors specific for inherited major histocompatibility complex class I (MHC-I) molecules. Current models imply that NK cell education requires an interaction of inhibitory receptors with MHC-I expressed on other cells. However, the inhibitory Ly49A receptor can also bind MHC-I ligand on the NK cell itself (in cis). Here we describe a Ly49A variant, which can engage MHC-I expressed on other cells but not in cis. Even though this variant inhibited NK cell effector function, it failed to educate NK cells. The association with MHC-I in cis sequestered wild-type Ly49A, and this was found to relieve NK cells from a suppressive effect of unengaged Ly49A. These data explain how inhibitory MHC-I receptors can facilitate NK cell activation. They dissociate classical inhibitory from educating functions of Ly49A and suggest that cis interaction of Ly49A is necessary for NK cell education.

PU.1 is a hematopoietic-specific transcriptional activator that is absolutely required for the differentiation of B lymphocytes and myeloid-lineage cells. Although PU.1 is also expressed by early erythroid progenitor cells, its role in erythropoiesis, if any, is unknown. To investigate the relevance of PU.1 in erythropoiesis, we produced a line of PU.1-deficient mice carrying a green fluorescent protein reporter at this locus. We report here that PU.1 is tightly regulated during differentiation—it is expressed at low levels in erythroid progenitor cells and down-regulated upon terminal differentiation. Strikingly, PU.1-deficient fetal erythroid progenitors lose their self-renewal capacity and undergo proliferation arrest, premature differentiation, and apoptosis. In adult mice lacking one PU.1 allele, similar defects are detected following stress-induced erythropoiesis. These studies identify PU.1 as a novel and critical regulator of erythropoiesis and highlight the versatility of this transcription factor in promoting or preventing differentiation depending on the hematopoietic lineage.