Lymphoid enhancer factor 1 (LEF-1) is a sequence-specific DNA-binding protein that is expressed in pre-B and T lymphocytes of adult mice, and in the neural crest, mesencephalon, tooth germs, whisker follicles, and other sites during embryogenesis. We have generated mice carrying a homozygous germ-line mutation in the LEF-1 gene that eliminates its protein expression and causes postnatal lethality. The mutant mice lack teeth, mammary glands, whiskers, and hair but show no obvious defects in lymphoid cell populations at birth. The I£F-l-deficient mice also lack the mesencephalic nucleus of the trigeminal nerve, the only neural crest-derived neurons normally present within the brain, but no deficiency can be detected in other neural crest-derived neuronal populations. Together, the pattern of these defects suggest an essential role for LEF-1 in the formation of several organs and structures that require inductive tissue interactions.

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Schistosomiasis (bilharzia) is a parasitic disease caused by several species of schistosome worms (blood flukes). The key pathogenic event in this disease is the formation of granulomas around schistosome eggs trapped in portal venules of the liver. Granulomas are a distinctive form of chronic inflammation characterized by localized aggregation of activated macrophages around an inciting stimulus. Each granuloma evolves to form a fibrous scar; in schistosomiasis, the result is widespread hepatic fibrosis and portal hypertension. To identify the specific immune signal molecules necessary for granuloma formation, we studied schistosome infections in severe combined immunodeficient (SCID) mice, which have normal macrophages but lack functional B or T lymphocytes. Here we report that the immunoregulatory cytokine tumour necrosis factor alpha is necessary and sufficient to reconstitute granuloma formation in schistosome-infected SCID mice. Moreover, we find that the parasitic worms require tumour necrosis factor alpha for egg-laying and for excretion of eggs from the host. The implication of this latter result is that the parasite has adapted so successfully to its host that it uses a host-derived immunoregulatory protein as a signal for replication and transmission.

The human immunodeficiency virus type 1 (HIV-1) transactivator Rev is a nuclear protein that regulates expression of certain HIV-1 transcripts by binding to an RNA target element (the RRIE) present in these transcripts. A short arginine-rich sequence in Rev contains the signals required to direct this protein into nuclei, where it associates preferentially with nucleoli. We created a steroid-inducible transactivator by fusing Rev with the steroid-binding domain of the glucocorticoid receptor (GR). This Rev/GR protein remains inactive in the cytoplasm when steroids are absent, but it enters the nucleus and initiates transactivatlon within minutes after exposure to dexamethasone. Although the GR moiety is sufficient to transport Rev/GR into nuclei, mutation of certain residues in the arginine-rich region blocks nucleolar localization and also inhibits transactivation. We find that other mutations in this region, however, can abolish the function of Rev/GR without affecting its localization; the latter phenotype may reflect a specific defect in binding of the RRE.The rev gene of human immunodeficiency virus type 1 (HIV-1) encodes a 116-amino acid regulatory protein that transactivates the expression of other essential HIV-1 genes (1, 2). Localized in the nuclei of infected cells, where it associates preferentially with nucleoli (3), Rev acts at the posttranscriptional level by inducing the export of incompletely spliced viral mRNAs to the cytoplasm (1, 2, 4-8). The mechanism ofthis transactivation is not fully understood, but it is thought to depend on the binding of Rev protein to an array of RNA hairpin loops (termed the Rev response element, RRE) situated within the target HIV-1 transcripts (9)(10)(11)(12)(13)(14).The signals that direct Rev protein into nuclei are contained in a short basic region of the protein (approximately amino acids 25-50) that is rich in arginine residues (15, 16). Mutations in this basic region inhibit the nuclear accumulation of Rev and produce a concomitant defect in transactivation, implying that Rev must enter the nucleus to exert its effects. Although recent reports suggest that this region also harbors sequences that target Rev to nucleoli (17, 18) or participate in binding of the RRE (19), it has been difficult to evaluate these activities by conventional mutagenic analysis in vivo because of the need to maintain efficient nuclear translocation. We now describe studies of a Rev fusion protein whose entry into the nucleus is controlled by sequences from the glucocorticoid receptor (GR). This Rev/GR protein exhibits steroid-dependent Rev activity and thus provides the basis for an inducible system in which to study the dynamics of Rev transactivation. Moreover, because the GR moiety is sufficient to direct this protein into nuclei, mutational analysis ofRev/GR has enabled us to evaluate the functions of the basic region independently of any effect on nuclear translocation. Our findings illuminate the critical and complex role of this region in the localization and function ...

A homozygous mutation in the kinase domain of ZAP-70, a T cell receptor-associated protein tyrosine kinase, produced a distinctive form of human severe combined immunodeficiency. Manifestations of this disorder included profound immunodeficiency, absence of peripheral CD8+ T cells, and abundant peripheral CD4+ T cells that were refractory to T cell receptor-mediated activation. These findings demonstrate that ZAP-70 is essential for human T cell function and suggest that CD4+ and CD8+ T cells depend on different intracellular signaling pathways to support their development or survival.